Substituted imidazopyrimidin-5(6h)-ones as allosteric modulators of mglur5 receptors

ABSTRACT

In one aspect, the invention relates to imidazopyrimidin-5(6H)-one analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/452,921, filed on Mar. 15, 2011, which is incorporated herein byreference in its entirety.

ACKNOWLEDGMENT

This invention was made with government support under grant numbersMH062646, MH073676 and MH082867 awarded by the National Institute ofMental Health (NIMH), and under grant number NS031373 awarded by theNational Institute of Neurological Disorders and Stroke. The UnitedStates government has certain rights in the invention.

BACKGROUND

Glutamate (L-glutamic acid) is the major excitatory transmitter in themammalian central nervous system, exerting its effects through bothionotropic and metabotropic glutamate receptors. The metabotropicglutamater receptors (mGluRs) belong to family C (also known as family3) of the G-protein-coupled receptors (GPCRs). They are characterized bya seven transmembrane (7TM) α-helical domain connected via a cysteinerich-region to a large bi-lobed extracellular amino-terminal domain(FIG. 3). While the orthosteric binding site is contained in theamino-terminal domain, currently known allosteric binding sites residein the 7TM domain. The mGluR family comprises eight known mGluRsreceptor types (designated as mGluR1 through mGluR8). Several of thereceptor types are expressed as specific splice variants, e.g. mGluR5aand mGluR5b or mGluR8a, mGluR8b and mGluR8c. The family has beenclassified into three groups based on their structure, preferred signaltransduction mechanisms, and pharmacology.

Group I receptors (mGluR1 and mGluR5) are coupled to Gαq, a process thatresults in stimulation of phospholipase C and an increase inintracellular calcium and inositol phosphate levels. Group II receptors(mGluR2 and mGluR3) and group III receptors (mGluR4, mGluR6, mGluR7, andmGluR8) are coupled to Gαi, which leads to decreases in cyclic adenosinemonophosphate (cAMP) levels. While the Group I receptors arepredominately located postsynaptically and typically enhancepostsynaptic signaling, the group II and III receptors are locatedpresynaptically and typically have inhibitory effects onneurotransmitter release.

Without wishing to be bound by a particular theory, metabotropicglutamate receptors, including mGluR5, have been implicated in a widerange of biological functions, indicating a potential role for themGluR5 receptor in a variety of disease processes in mammals. Ligands ofmetabotropic glutamate receptors can be used for the treatment orprevention of acute and/or chronic neurological and/or psychiatricdisorders associated with glutamate dysfunction, such as psychosis,schizophrenia, age-related cognitive decline, and the like. Further,without wishing to be bound by theory, increasing evidence indicatesmGluRs play an important role in lasting changes in synaptictransmission, and studies of synaptic plasticity in the Fmr1 knockoutmouse have identified a connection between the fragile X phenotype andmGluR signaling.

The identification of small molecule mGluR agonists that bind at theorthosteric site has greatly increased the understanding of the rolesplayed by these receptors and their corresponding relation to disease.Because the majority of these agonists were designed as analogs ofglutamate, they typically lack the desired characteristics for drugstargeting mGluR such as oral bioavailability and/or distribution to thecentral nervous system (CNS). Moreover, because of the highly conservednature of the glutamate binding site, most orthosteric agonists lackselectivity among the various mGluRs.

Selective positive allosteric modulators (“PAMs”) are compounds that donot directly activate receptors by themselves, but binding of thesecompounds potentiates the response of the receptor to glutamate or otherorthosteric agonists by either increasing the affinity of an orthostericagonist at the orthosteric binding site or enhancing coupling to theG-protein or both. PAMs are thus an attractive mechanism for enhancingappropriate physiological receptor activation.

Unfortunately, there is a scarcity of selective positive allostericmodulators for the mGluR5 receptor. Further, conventional mGluR5receptor modulators typically lack satisfactory aqueous solubility andexhibit poor oral bioavailability. Therefore, there remains a need formethods and compositions that overcome these deficiencies and thateffectively provide selective positive allosteric modulators for themGluR5 receptor.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompounds useful as positive allosteric modulators (i.e., potentiators)of the metabotropic glutamate receptor subtype 5 (mGluR5), methods ofmaking same, pharmaceutical compositions comprising same, and methods oftreating neurological and psychiatric disorders associated withglutamate dysfunction using same.

Disclosed are compounds having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a disclosed compound and apharmaceutically acceptable carrier.

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein Ar¹ is phenyl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclic heteroarylsubstituted with 0-3 substituents independently selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) isselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein R³ is selected from phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ ismonocyclic heteroaryl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R⁴ is selected fromhydrogen, halogen, cyano, and C1-C4 alkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen and C1-C4 alkyl; whereinR^(1a) and R^(2a) are optionally covalently bonded and, together withthe intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkyl, and (b) hydrogenating the compound, therebyyielding a compound having a structure represented by a formula:

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2C); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R⁴ is selected from hydrogen,halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkylamino, C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each ofR^(5a) and R^(5b) is independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, and (b) reacting thecompound with R³X, wherein X is a leaving group, and wherein R³, when----- is present, is selected from hydrogen, C1-C6 alkyl; C1-C6alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl;C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and wherein R³, when ----- is not present, is Ar²; thereby substitutingat the amide.

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R⁴ is selected from hydrogen,halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkylamino, C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each ofR^(5a) and R^(5b) is independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, and (b) coupling thecompound with R³X, in the presence of a coupling reagent, wherein X isbromo or iodo, and wherein R³, when is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and wherein R³, when is not present, isAr²; thereby substituting at the amide.

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein X is a leaving group; wherein ----- is an optional covalentbond, wherein valence is satisfied; wherein when ----- is present and A¹and A² are joined by a covalent double bond, A¹ is CR^(1a), and A² isCR^(2a); wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selectedfrom hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is not present and A¹ and A² arejoined by a covalent single bond, A¹ is CR^(1b)R^(1c), and A² isCR^(2b)R^(2c); wherein each of R^(1b) and R^(1c) are independentlyselected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl, or R^(1b) and R^(1c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein R^(1a) and R^(2a), whenpresent, are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkenyl; wherein R^(1b) and R^(2b), when present, areoptionally covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered fused cycloalkyl;wherein R³, when ----- is present, is selected from hydrogen, C1-C6alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-;(C3-C8 heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; whereinAr² is phenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, and (b) reacting the compound with Ar¹OH,wherein Ar¹ is phenyl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclic heteroarylsubstituted with 0-3 substituents independently selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl, thereby yielding a compound having a structurerepresented by a formula:

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and reacting the compound with a compound represented by the formula:

wherein R⁴ is selected from hydrogen, halogen, cyano, and C1-C4 alkyl;and wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen and C1-C4 alkyl.

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, and (b) reacting the compoundwith a compound represented by a formula:

wherein R⁴ is selected from hydrogen, halogen, cyano, and C1-C4 alkyl;and wherein each of R^(5a) and R^(5b) is independently selected fromselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl.

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein Ar¹ is phenyl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclic heteroarylsubstituted with 0-3 substituents independently selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, and (b) hydrogenating the compound, therebyyielding a compound having a structure represented by a formula:

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein when ----- is present and A¹ and A² are joined by a covalentdouble bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a) isselected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl;C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) halogenating the compound by reaction with N-halosuccinimide.

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein Ar¹ is phenyl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclic heteroarylsubstituted with 0-3 substituents independently selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when is notpresent and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl;C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) halogenating the compound by reaction with N-halosuccinimide.

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein X is halogen; wherein Ar¹ is phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ ismonocyclic heteroaryl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when ----- is presentand A¹ and A² are joined by a covalent double bond, A¹ is CR^(1a), andA² is CR^(2a); wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) isselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is not present and A¹ and A² arejoined by a covalent single bond, A¹ is CR^(1b)R^(1c), and A² isCR^(2b)R^(2c); wherein each of R^(1b) and R^(1c) are independentlyselected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl, or R^(1b) and R^(1c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein R^(1a) and R^(2a), whenpresent, are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkenyl; wherein R^(1b) and R^(2b), when present, areoptionally covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered fused cycloalkyl;wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) reacting the compound with R⁶OH in the presence of a base, whereinR⁶ is C1-C4 alkyl, thereby yielding a compound having a structurerepresented by a formula:

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein X is halogen; wherein Ar¹ is phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ ismonocyclic heteroaryl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when ----- is presentand A¹ and A² are joined by a covalent double bond, A¹ is CR^(1a), andA² is CR^(2a); wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) isselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is not present and A¹ and A² arejoined by a covalent single bond, A¹ is CR^(1b)R^(1c), and A² isCR^(2b)R^(2c); wherein each of R^(1b) and R^(1c) are independentlyselected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl, or R^(1b) and R^(1c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein R^(1a) and R^(2a), whenpresent, are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkenyl; wherein R^(1b) and R^(2b), when present, areoptionally covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered fused cycloalkyl;wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) reacting the compound with NR⁷R⁸ in the presence of a metalcatalyst, wherein each of R⁷ and R⁷ are independently selected from Hand C1-C4 alkyl, thereby yielding a compound having a structurerepresented by a formula:

Also disclosed are synthetic methods comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein X is halogen; wherein Ar¹ is phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ ismonocyclic heteroaryl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when ----- is presentand A¹ and A² are joined by a covalent double bond, A¹ is CR^(1a), andA² is CR^(2a); wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) isselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is not present and A¹ and A² arejoined by a covalent single bond, A¹ is CR^(1b)R^(1c), and A² isCR^(2b)R^(2c); wherein each of R^(1b) and R^(1c) are independentlyselected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl, or R^(1b) and R^(1c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein R^(1a) and R^(2a), whenpresent, are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkenyl; wherein R^(1b) and R^(2b), when present, areoptionally covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered fused cycloalkyl;wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) reacting the compound with R⁹B(OH)₂ in the presence of a metalcatalyst, wherein R⁹ is selected from C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl thereby yielding a compound having a structurerepresented by a formula:

Disclosed are methods for the treatment of a neurological and/orpsychiatric disorder associated with glutamate dysfunction in a mammalcomprising the step of administering to the mammal a therapeuticallyeffective amount of at least one compound having a structure representedby a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c) and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

Also disclosed are methods for the treatment of a disease ofuncontrolled cellular proliferation in a mammal comprising the step ofadministering to the mammal a therapeutically effective amount of atleast one compound having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

Also disclosed are methods for potentiation of metabotropic glutamatereceptor activity in a mammal comprising the step of administering tothe mammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

Also disclosed are methods for partial agonism of metabotropic glutamatereceptor activity in a mammal comprising the step of administering tothe mammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

Also disclosed are methods for enhancing cognition in a mammalcomprising the step of administering to the mammal an effective amountof at least one compound having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

Also disclosed are methods for modulating mGluR5 activity in a mammalcomprising the step of administering to the mammal an effective amountof at least one compound having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

Also disclosed are methods modulating mGluR5 activity in at least onecell, comprising the step of contacting the at least one cell with aneffective amount of at least one compound having a structure representedby a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

Also disclosed are kits comprising at least one compound having astructure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof, and one or more of: (a) at least one agent knownto increase mGluR5 activity; (b) at least one agent known to decreasemGluR5 activity; (c) at least one agent known to treat a neurologicaland/or psychiatric disorder; (d) at least one agent known to treat adisease of uncontrolled cellular proliferation; or (e) instructions fortreating a disorder associated with glutamate dysfunction.

Also disclosed are methods for manufacturing a medicament comprisingcombining at least one disclosed compound or at least one disclosedproduct with a pharmaceutically acceptable carrier or diluent.

Also disclosed are uses of a disclosed compound or a disclosed productin the manufacture of a medicament for the treatment of a disorderassociated with glutamate dysfunction in a mammal.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows a schematic of the NMDA receptor.

FIG. 2 shows a schematic illustrating that activation of mGluR5potentiates NMDA receptor function.

FIG. 3 shows a schematic illustrating structural features of mGluR5 andallosteric binding.

FIG. 4 shows a representative study demonstrating the dose-dependentreversal of amphetamine-induced hyperlocomotion by a representativedisclosed compound.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedherein can be different from the actual publication dates, which canrequire independent confirmation.

A. DEFINITIONS

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or can not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “allosteric site” refers to a ligand bindingsite that is topographically distinct from the orthosteric binding site.

As used herein, the term “modulator” refers to a molecular entity (e.g.,but not limited to, a ligand and a disclosed compound) that modulatesthe activity of the target receptor protein.

As used herein, the term “ligand” refers to a a natural or syntheticmolecular entity that is capable of associating or binding to a receptorto form a complex and mediate, prevent or modify a biological effect.Thus, the term “ligand” encompasses allosteric modulators, inhibitors,activators, agonists, antagonists, natural substrates and analogs ofnatural substrates.

As used herein, the terms “natural ligand” and “endogenous ligand” areused interchangeably, and refer to a naturally occurring ligand, foundin nature, which binds to a receptor.

As used herein, the term “orthosteric site” refers to the primarybinding site on a receptor that is recognized by the endogenous ligandor agonist for that receptor. For example, the orthosteric site in themGluR5 receptor is the site that glutamate binds.

As used herein, the term “mGluR5 receptor positive allosteric modulator”refers to any exogenously administered compound or agent that directlyor indirectly augments the activity of the mGluR5 receptor in thepresence or in the absence of glutamate in an animal, in particular amammal, for example a human. In one aspect, a mGluR5 receptor positiveallosteric modulator increases the activity of the mGluR5 receptor in acell in the presence of extracellular glutamate. The cell can be humanembryonic kidney cells transfected with human mGluR5. The cell can behuman embryonic kidney cells transfected with rat mGluR5. The cell canbe human embryonic kidney cells transfected with a mammalian mGluR5 Theterm “mGluR5 receptor positive allosteric modulator” includes a compoundthat is a “mGluR5 receptor allosteric potentiator” or a “mGluR5 receptorallosteric agonist,” as well as a compound that has mixed activitycomprising pharmacology of both an “mGluR5 receptor allostericpotentiator” and an “mGluR5 receptor allosteric agonist”. The term“mGluR5 receptor positive allosteric modulator also includes a compoundthat is a “mGluR5 receptor allosteric enhancer.”

As used herein, the term “mGluR5 receptor allosteric potentiator” refersto any exogenously administered compound or agent that directly orindirectly augments the response produced by the endogenous ligand (suchas glutamate) when the endogenous ligand binds to the orthosteric siteof the mGluR5 receptor in an animal, in particular a mammal, for examplea human. The mGluR5 receptor allosteric potentiator binds to a siteother than the orthosteric site, that is, an allosteric site, andpositively augments the response of the receptor to an agonist or theendogenous ligand. In one aspect, an allosteric potentiator does notinduce desensitization of the receptor, activity of a compound as anmGluR5 receptor allosteric potentiator provides advantages over the useof a pure mGluR5 receptor allosteric agonist. Such advantages caninclude, for example, increased safety margin, higher tolerability,diminished potential for abuse, and reduced toxicity.

As used herein, the term “mGluR5 receptor allosteric enhancer” refers toany exogenously administered compound or agent that directly orindirectly augments the response produced by the endogenous ligand in ananimal, in particular a mammal, for example a human. In one aspect, theallosteric enhancer increases the affinity of the natural ligand oragonist for the orthosteric site. In another aspect, an allostericenhancer increases the agonist efficacy. The mGluR5 receptor allostericenhancer binds to a site other than the orthosteric site, that is, anallosteric site, and positively augments the response of the receptor toan agonist or the endogenous ligand. An allosteric enhancer has noeffect on the receptor by itself and requires the presence of an agonistor the natural ligand to realize a receptor effect.

As used herein, the term “mGluR5 receptor allosteric agonist” refers toany exogenously administered compound or agent that directly activatesthe activity of the mGluR5 receptor in the absence of the endogenousligand (such as glutamate) in an animal, in particular a mammal, forexample a human. The mGluR5 receptor allosteric agonist binds to a sitethat is distinct from the orthosteric glutamate site of the mGluR5.Because it does not require the presence of the endogenous ligand,activity of a compound as an mGluR5 receptor allosteric agonist providesadvantages over the use of a pure mGluR5 receptor allostericpotentiator, such as more rapid onset of action.

As used herein, the term “mGluR5 receptor neutral allosteric ligand”refers to any exogenously administered compound or agent that binds toan allosteric site without affecting the binding or function of agonistsor the natural ligand at the orthosteric site in an animal, inparticular a mammal, for example a human. However, a neutral allostericligand can block the action of other allosteric modulators that act viathe same site.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects. In some aspects of the disclosedmethods, the subject has been diagnosed with a need for treatment of oneor more neurological and/or psychiatric disorder associated withglutamate dysfunction prior to the administering step. In some aspectsof the disclosed method, the subject has been diagnosed with a need forpositive allosteric modulation of metabotropic glutamate receptoractivity prior to the administering step. In some aspects of thedisclosed method, the subject has been diagnosed with a need for partialagonism of metabotropic glutamate receptor activity prior to theadministering step.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with a disorder treatable by modulation of mGluR5” meanshaving been subjected to a physical examination by a person of skill,for example, a physician, and found to have a condition that can bediagnosed or treated by a compound or composition that can modulatemGluR5. As a further example, “diagnosed with a need for modulation ofmGluR5” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditioncharacterized by mGluR5 activity. Such a diagnosis can be in referenceto a disorder, such as a neurodegenerative disease, and the like, asdiscussed herein. For example, the term “diagnosed with a need forpositive allosteric modulation of metabotropic glutamate receptoractivity” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditionthat can be diagnosed or treated by positive allosteric modulation ofmetabotropic glutamate receptor activity. For example, “diagnosed with aneed for partial agonism of metabotropic glutamate receptor activity”means having been subjected to a physical examination by a person ofskill, for example, a physician, and found to have a condition that canbe diagnosed or treated by partial agonism of metabotropic glutamatereceptor activity. For example, “diagnosed with a need for treatment ofone or more neurological and/or psychiatric disorder associated withglutamate dysfunction” means having been subjected to a physicalexamination by a person of skill, for example, a physician, and found tohave one or more neurological and/or psychiatric disorder associatedwith glutamate dysfunction.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto mGluR5 activity) based upon an earlier diagnosis by a person of skilland thereafter subjected to treatment for the disorder. It iscontemplated that the identification can, in one aspect, be performed bya person different from the person making the diagnosis. It is alsocontemplated, in a further aspect, that the administration can beperformed by one who subsequently performed the administration.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

The term “contacting” as used herein refers to bringing a disclosedcompound and a cell, target metabotropic glutamate receptor, or otherbiological entity together in such a manner that the compound can affectthe activity of the target (e.g., spliceosome, cell, etc.), eitherdirectly; i.e., by interacting with the target itself, or indirectly;i.e., by interacting with another molecule, co-factor, factor, orprotein on which the activity of the target is dependent.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side affects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “kit” means a collection of at least two componentsconstituting the kit. Together, the components constitute a functionalunit for a given purpose. Individual member components may be physicallypackaged together or separately. For example, a kit comprising aninstruction for using the kit may or may not physically include theinstruction with other individual member components. Instead, theinstruction can be supplied as a separate member component, either in apaper form or an electronic form which may be supplied on computerreadable memory device or downloaded from an internet website, or asrecorded presentation.

As used herein, “instruction(s)” means documents describing relevantmaterials or methodologies pertaining to a kit. These materials mayinclude any combination of the following: background information, listof components and their availability information (purchase information,etc.), brief or detailed protocols for using the kit, trouble-shooting,references, technical support, and any other related documents.Instructions can be supplied with the kit or as a separate membercomponent, either as a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from aninternet website, or as recorded presentation. Instructions can compriseone or multiple documents, and are meant to include future updates.

As used herein, the terms “therapeutic agent” include any synthetic ornaturally occurring biologically active compound or composition ofmatter which, when administered to an organism (human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, vaccines, and biopharmaceuticals including molecules such asproteins, peptides, hormones, nucleic acids, gene constructs and thelike. Examples of therapeutic agents are described in well-knownliterature references such as the Merck Index (14 th edition), thePhysicians' Desk Reference (64 th edition), and The PharmacologicalBasis of Therapeutics (12 th edition), and they include, withoutlimitation, medicaments; vitamins; mineral supplements; substances usedfor the treatment, prevention, diagnosis, cure or mitigation of adisease or illness; substances that affect the structure or function ofthe body, or pro-drugs, which become biologically active or more activeafter they have been placed in a physiological environment. For example,the term “therapeutic agent” includes compounds or compositions for usein all of the major therapeutic areas including, but not limited to,adjuvants; anti-infectives such as antibiotics and antiviral agents;analgesics and analgesic combinations, anorexics, anti-inflammatoryagents, anti-epileptics, local and general anesthetics, hypnotics,sedatives, antipsychotic agents, neuroleptic agents, antidepressants,anxiolytics, antagonists, neuron blocking agents, anticholinergic andcholinomimetic agents, antimuscarinic and muscarinic agents,antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, andnutrients, antiarthritics, antiasthmatic agents, anticonvulsants,antihistamines, antinauseants, antineoplastics, antipruritics,antipyretics; antispasmodics, cardiovascular preparations (includingcalcium channel blockers, beta-blockers, beta-agonists andantiarrythmics), antihypertensives, diuretics, vasodilators; centralnervous system stimulants; cough and cold preparations; decongestants;diagnostics; hormones; bone growth stimulants and bone resorptioninhibitors; immunosuppressives; muscle relaxants; psychostimulants;sedatives; tranquilizers; proteins, peptides, and fragments thereof(whether naturally occurring, chemically synthesized or recombinantlyproduced); and nucleic acid molecules (polymeric forms of two or morenucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA)including both double- and single-stranded molecules, gene constructs,expression vectors, antisense molecules and the like), small molecules(e.g., doxorubicin) and other biologically active macromolecules suchas, for example, proteins and enzymes. The agent may be a biologicallyactive agent used in medical, including veterinary, applications and inagriculture, such as with plants, as well as other areas. The termtherapeutic agent also includes without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of disease or illness; orsubstances which affect the structure or function of the body; orpro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%activation or enhancement of a biological process, or component of aprocess. For example, EC₅₀ can refer to the concentration of agonistthat provokes a response halfway between the baseline and maximumresponse in an in vitro assay. For example, an EC₅₀ for mGluR5 receptorcan be determined in an in vitro or cell-based assay system. Such invitro assay systems frequently utilize a cell line that either expressesendogenously a target of interest, or has been transfected with asuitable expression vector that directs expression of a recombinant formof the target such as mGluR5. For example, the EC₅₀ for mGluR5 can bedetermined using human embryonic kidney (HEK) cells transfected withhuman mGluR5. Alternatively, the EC₅₀ for mGluR5 can be determined usinghuman embryonic kidney (HEK) cells transfected with rat mGluR5. Inanother example, the EC₅₀ for mGluR5 can be determined using humanembryonic kidney (HEK) cells transfected with a mammalian mGluR5.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process. Forexample, IC₅₀ refers to the half maximal (50%) inhibitory concentration(IC) of a substance as determined in a suitable assay. For example, anIC₅₀ for mGluR5 receptor can be determined in an in vitro or cell-basedassay system. Frequently, receptor assays, including suitable assays formGluR5, make use of a suitable cell-line, e.g. a cell line that eitherexpresses endogenously a target of interest, or has been transfectedwith a suitable expression vector that directs expression of arecombinant form of the target such as mGluR5. For example, the IC₅₀ formGluR5 can be determined using human embryonic kidney (HEK) cellstransfected with human mGluR5. Alternatively, the IC₅₀ for mGluR5 can bedetermined using human embryonic kidney (HEK) cells transfected with ratmGluR5. In another example, the IC₅₀ for mGluR5 can be determined usinghuman embryonic kidney (HEK) cells transfected with a mammalian mGluR5.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. It isunderstand that the alkyl group is acyclic. The alkyl group can bebranched or unbranched. The alkyl group can also be substituted orunsubstituted. For example, the alkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein. A “lower alkyl” group is an alkyl group containingfrom one to six (e.g., from one to four) carbon atoms. The term alkylgroup can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl,C105 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10alkyl, and the like up to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The cycloalkyl group can besubstituted or unsubstituted. The cycloalkyl group can be substitutedwith one or more groups including, but not limited to, alkyl,cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The cycloalkenyl group can be substituted orunsubstituted. The cycloalkenyl group can be substituted with one ormore groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The cycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group can be substituted with one or more groups including,but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylicacid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl,sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the π clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl refers to two aryl groups thatare bound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “alkylamino” as used herein is represented by the formulas—NH(-alkyl) and —N(-alkyl)₂, and where alkyl is as described herein. Thealkyl group can be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl,C105 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10alkyl, and the like, up to and including a C1-C24 alkyl. Representativeexamples include, but are not limited to, methylamino group, ethylaminogroup, propylamino group, isopropylamino group, butylamino group,isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group,pentylamino group, isopentylamino group, (tert-pentyl)amino group,hexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylaminogroup, and N-ethyl-N-propylamino group. Representative examples include,but are not limited to, dimethylamino group, diethylamino group,dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group, and the like.

The term “monoalkylamino” as used herein is represented by the formula—NH(-alkyl), where alkyl is as described herein. The alkyl group can bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C105 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and thelike, up to and including a C1-C24 alkyl. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂, where alkyl is as described herein. The alkyl group can bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C105 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and thelike, up to and including a C1-C24 alkyl. It is understood that eachalkyl group can be independently varied, e.g. as in the representativecompounds such as N-ethyl-N-methylamino group, N-methyl-N-propylaminogroup, and N-ethyl-N-propylamino group. Representative examples include,but are not limited to, dimethylamino group, diethylamino group,dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group, and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an interger from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen,” or “halide,” as used herein can be usedinterchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl,” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl,” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted, and the heteroaryl group canbe monocyclic, bicyclic or multicyclic aromatic ring. The heteroarylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy,nitro, silyl, sulfo-oxo, or thiol as described herein. It is understoodthat a heteroaryl group may be bound either through a heteroatom in thering, where chemically possible, or one of carbons comprising theheteroaryl ring.

A variety of heteroaryl groups are known in the art and include, withoutlimitation, oxygen-containing rings, nitrogen-containing rings,sulfur-containing rings, mixed heteroatom-containing rings, fusedheteroatom containing rings, and combinations thereof. Non-limitingexamples of heteroaryl rings include furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,azepinyl, triazinyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl,oxatriazolyl, oxepinyl, thiepinyl, diazepinyl, benzofuranyl,thionapthene, indolyl, benzazolyl, pyranopyrrolyl, isoindazolyl,indoxazinyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzodiazonyl,naphthyridinyl, benzothienyl, pyridopyridinyl, acridinyl, carbazolyl andpurinyl rings.

The term “monocyclic heteroaryl,” as used herein, refers to a monocyclicring system which is aromatic and in which at least one of the ringatoms is a heteroatom. Monocyclic heteroaryl groups include, but are notlimited, to the following exemplary groups: pyridine, pyrimidine,pyridazine, pyrazine, furan, thiophene, pyrrole, isoxazole, isothiazole,pyrazole, oxazole, thiazole, imidazole, oxadiazole, including,1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, triazine, including1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, and the like. Monocyclic heteroaryl groups arenumbered according to standard chemical nomenclature.

The term “bicyclic heteroaryl,” as used herein, refers to a ring systemcomprising a bicyclic ring system in which at least one of the two ringsis aromatic and at least one of the two rings contains a heteroatom.Bicyclic heteroaryl encompasses ring systems wherein an aromatic ring isfused with another aromatic ring, or wherein an aromatic ring is fusedwith a non-aromatic ring. Bicyclic heteroaryl encompasses ring systemswherein a benzene ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5-or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Examples ofbicyclic heteroaryl groups include without limitation indolyl,isoindolyl, indolyl, indolinyl, indolizinyl, quinolinyl, isoquinolinyl,benzofuryl, bexothiophenyl, indazolyl, benzimidazolyl, benzothiazinyl,benzothiazolyl, purinyl, quinolizyl, quinolyl, isoquinolyl, cinnolinyl,phthalazinyl, quinazolizinyl, quinoxalyl, naphthyridinyl, and pteridyl.Bicyclic heteroaryls are numbered according to standard chemicalnomenclature.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems where at least one of the carbon atoms of the ring is replacedwith a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur,or phosphorus. A heterocycloalkyl can include one to four heteroatomsindependently selected from oxygen, nitrogen, and sulfur, wherein anitrogen and sulfur heteroatom optionally can be oxidized and a nitrogenheteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited, to the followingexemplary groups: pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, andtetrahydrofuryl. The term heterocycloalkyl group can also be a C2heterocycloalkyl, C2-C3 heterocycloalkyl, C2-C4 heterocycloalkyl, C2-C5heterocycloalkyl, C2-C6 heterocycloalkyl, C2-C7 heterocycloalkyl, C2-C8heterocycloalkyl, C2-C9 heterocycloalkyl, C2-C10 heterocycloalkyl,C2-C11 heterocycloalkyl, and the like up to and including a C2-C14heterocycloalkyl. For example, a C2 heterocycloalkyl comprises a groupwhich has two carbon atoms and at least one heteroatom, including, butnot limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and thelike. Alternatively, for example, a C5 heterocycloalkyl comprises agroup which has five carbon atoms and at least one heteroatom,including, but not limited to, piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, diazepanyl, and the like. It is understood that aheterocycloalkyl group may be bound either through a heteroatom in thering, where chemically possible, or one of carbons comprising theheterocycloalkyl ring. The heterocycloalkyl group can be substituted orunsubstituted. The heterocycloalkyl group can be substituted with one ormore groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “hydroxyl” or “hydroxy” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄—CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄—O—(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR—, —SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o);—(CH₂)₀₋₄C(O)NR^(o) ₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —(CH₂)₀₋₄OC(O)NR^(o)₂; —C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o),—(CH₂)₀₋₄S(O)₂OR^(o), —CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR^(o);—(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o);—N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o))₂; SiR^(o) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R., -(haloR.), —(CH₂)₀₋₂OH,—(CH₂)₀₋₂OR., —(CH₂)₀₋₂CH(OR.)₂; —O(haloR.), —CN, —N₃, —(CH₂)₀₋₂C(O)R.,—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR., —(CH₂)₀₋₂SR., —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR., —(CH₂)₀₋₂NR.₂, —NO₂, —SiR.₃, —OSiR.₃,—C(O)SR., —(C₁₋₄ straight or branched alkylene)C(O)OR., or —SSR. whereineach R. is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently selected from C₁₋₄aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(o) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen, —R.,-(haloR.), —OH, —OR., —O(haloR.), —CN, —C(O)OH, —C(O)OR., —NH₂, —NHR.,—NR.₂, or —NO₂, wherein each R. is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and isindependently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R., -(haloR.), —OH, —OR., —O(haloR.), —CN, —C(O)OH, —C(O)OR.,—NH₂, —NHR., —NR^() ₂, or —NO₂, wherein each R. is unsubstituted orwhere preceded by “halo” is substituted only with one or more halogens,and is independently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, and brosylate.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitatation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1-26 carbon atoms, 1 to 18carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbonatoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect,an organic residue can comprise 2-26 carbon atoms, 2 to 18 carbon atoms,2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has the structure

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1 to 15, carbon atoms, 1-12 carbonatoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In afurther aspect, an organic radical can have 2-26 carbon atoms, 2-18carbon atoms, 2 to 15 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms,2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often havehydrogen bound to at least some of the carbon atoms of the organicradical. One example, of an organic radical that comprises no inorganicatoms is a 5,6,7,8-tetrahydro-2-naphthyl radical. In some embodiments,an organic radical can contain 1-10 inorganic heteroatoms bound theretoor therein, including halogens, oxygen, sulfur, nitrogen, phosphorus,and the like. Examples of organic radicals include but are not limitedto an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy,carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl,alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy,haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic,or substituted heterocyclic radicals, wherein the terms are definedelsewhere herein. A few non-limiting examples of organic radicals thatinclude heteroatoms include alkoxy radicals, trifluoromethoxy radicals,acetoxy radicals, dimethylamino radicals and the like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound. Forexample, a compound prefixed with (−) or 1 meaning that the compound islevorotatory or a compound prefixed with (+) or d meaning that thecompound is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable minor images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Inglod-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labelled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³ C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et. al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. As another example, pyridinones canexist in two tautomeric forms, as shown below.

Unless stated to the contrary, the invention includes all such possibletautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

The following abbreviations are used herein. AcOEt: ethyl acetate. AcOH:acetic acid. ACN: acetonitrile. BuOH: 1-butanol. DIPEA or DIEA:N,N-diisopropylethylamine. DMAP: 4-dimethylaminopyridine. DCM:dichloromethane. DCE: 1,2-dichloroethane. DIPE: diisopropylether. DMF:N,N-dimethyl formamide. DMSO: dimethylsulfoxide. EDC:1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride. EtOH:ethanol. h: Hours. HPLC: high-performance liquid chromatography. HOBt:1-hydroxybenzotriazole. iPrOH: 2-propanol. LC-MS or LCMS: liquidchromatography/mass spectrometry. [M+H]+: protonated mass of the freebase of the compound. M.p.: melting point. MeOH: methanol. Min: Minutes.NMR: nuclear magnetic resonance. RP: reversed phase. Rt: retention time(in minutes). RT: Room temperature. TEA: triethylamine. THF:tetrahydrofuran. TMEDA: N,N,N′N′-tetramethylethylenediamine

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds can not be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. COMPOUNDS

In one aspect, the invention relates to compounds useful as positiveallosteric modulators of the metabotropic glutamate receptor subtype 5(mGluR5). More specifically, in one aspect, the present inventionrelates to compounds that allosterically modulate mGluR5 receptoractivity, affecting the sensitivity of mGluR5 receptors to agonistswithout acting as orthosteric agonists themselves. The compounds can, inone aspect, exhibit subtype selectivity.

In one aspect, the disclosed compounds exhibit positive allostericmodulation of mGluR5 response to glutamate as an increase in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In furtheraspect, the human embryonic kidney cells are transfected with humanmGluR5. In yet a further aspect, human embryonic kidney cells aretransfected with mGluR5 of a mammal.

In one aspect, the compounds of the invention are useful in thetreatment neurological and psychiatric disorders associated withglutamate dysfunction and other diseases in which metabotropic glutamatereceptors are involved, as further described herein.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In various aspects, s the invention relates to a compound having astructure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.

In one aspect, the invention relates to a compound having a structurerepresented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when is present and A¹ and A² are joined by acovalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(ic) and A² is CR^(2b)R^(2c); wherein each of R^(1b) and R^(1c)are independently selected from hydrogen, fluoro, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof, wherein the compound exhibitspotentiation of mGluR5 response to glutamate as an increase in responseto non-maximal concentrations of glutamate in human embryonic kidneycells transfected with mGluR5 in the presence of the compound, comparedto the response to glutamate in the absence of the compound.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

wherein R⁷ and R⁸ are independently selected from hydrogen and C1-C4alkyl.

In a further aspect, the compound has a structure represented by aformula:

wherein R⁶ is C1-C4 alkyl.

In a further aspect, the compound has a structure represented by aformula:

wherein R⁹ is selected from C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

wherein R³ is selected from C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; and (C3-C8heterocycloalkyl)-C1-C6 alkyl-.

In a further aspect, the compound has a structure represented by aformula:

wherein R⁷ and R⁸ are independently selected from hydrogen and C1-C4alkyl.

In a further aspect, the compound has a structure represented by aformula:

wherein R⁶ is C1-C4 alkyl.

In a further aspect, the compound has a structure represented by aformula:

wherein R⁹ is selected from C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl.

In a further aspect, the compound has a structure represented by aformula:

wherein R⁹ is selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl.

In a further aspect, the compound has a structure represented by aformula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl or monocyclic heteroaryl; each of whichmay be unsubstituted or substituted with 1-3 substituents independentlyselected from halogen, cyano, and C1-C4 alkyl; wherein when ----- ispresent and A¹ and A² are joined by a covalent double bond, wherein A¹is CR^(1a), and A² is CR^(2a); wherein R^(1a) and R^(2a) are eachselected from hydrogen and halogen; wherein when is not present and A¹and A² are joined by a covalent single bond, wherein A¹ is CH₂, and A²is CH₂; wherein R³, when ----- is present, is selected from Ar² and(Ar²)—C1-C4 alkyl; wherein Ar² is phenyl, which may be unsubstituted orsubstituted with 1-3 substituents independently selected from halogen,cyano and C1-C4 alkyl; or Ar² is monocyclic heteroaryl, which may beunsubstituted or substituted with 1-3 substituents independentlyselected from halogen, C1-C4 alkyl, C1-C4 alkyoxy, and mono- ordi-C1-C4-alkylamino; wherein R³, when ----- is not present, is Ar²; andwherein monocyclic heteroaryl is pyridinyl, pyrimidinyl, pyridazinyl orpyrazinyl.

In a further aspect, the compound has a structure represented by aformula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl, which may be unsubstituted orsubstituted with 1-3 substituents independently selected from halogen,cyano and C1-C4 alkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, wherein A¹ is CR^(1a), and A² isCR^(2a); wherein R^(1a) is selected from hydrogen and halogen and R^(2a)is hydrogen; wherein when ----- is not present and A¹ and A² are joinedby a covalent single bond, wherein A¹ is CH₂, and A² is CH₂; wherein R³,when ----- is present, is selected from phenyl or benzyl, wherein eachof which may be unsubstituted or substituted at the phenyl moiety with1-3 independently selected halogen substituents; or pyridinyl, which maybe unsubstituted or substituted with 1-3 substituents independentlyselected from halogen, C1-C4 alkyl, C1-C4 alkyoxy, and mono- ordi-C1-C4-alkylamino; and wherein R³, when ----- is not present, isphenyl, which may be unsubstituted or substituted at the phenyl moietywith 1-3 independently selected halogen substituents; or pyridinyl,which may be unsubstituted or substituted with 1-3 substituentsindependently selected from halogen, C1-C4 alkyl, C1-C4 alkyoxy, andmono- or di-C1-C4-alkylamino. In a further aspect, the compound has astructure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl, which may be unsubstituted orsubstituted with 1-3 independently selected halogen substituents;wherein when ----- is present and A¹ and A² are joined by a covalentdouble bond, wherein A¹ and A² are each CH; wherein when ----- is notpresent and A¹ and A² are joined by a covalent single bond, wherein A¹and A² are each CH₂; wherein R³, when is present, is selected fromphenyl or pyridinyl, each of which may be unsubstituted or substitutedwith 1-3 independently selected halogen substituents; and wherein R³,when ----- is not present, is phenyl or pyridinyl, each of which may beunsubstituted or substituted with 1-3 independently selected halogensubstituents.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl or monocyclic heteroaryl; each of which may beunsubstituted or substituted with 1-3 substituents independentlyselected from halogen, cyano, and C1-C4 alkyl; wherein R^(1a) and R^(2a)are each selected from hydrogen and halogen; and wherein R³ is selectedfrom Ar² and (Ar²)—C1-C4 alkyl; wherein Ar² is phenyl, which may beunsubstituted or substituted with 1-3 substituents independentlyselected from halogen, cyano and C1-C4 alkyl; or Ar² is monocyclicheteroaryl, which may be unsubstituted or substituted with 1-3substituents independently selected from halogen, C1-C4 alkyl, C1-C4alkyoxy, and mono- or di-C1-C4-alkylamino.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl, which may be unsubstituted or substituted with1-3 substituents independently selected from halogen, cyano and C1-C4alkyl; wherein R^(1a) is selected from hydrogen and halogen; and whereinR³ is selected from phenyl or benzyl, wherein each of which may beunsubstituted or substituted at the phenyl or benzyl moiety with 1-3independently selected halogen substituents; or pyridinyl, which may beunsubstituted or substituted with 1-3 substituents independentlyselected from halogen, C1-C4 alkyl, C1-C4 alkyoxy, and mono- ordi-C1-C4-alkylamino.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl, which may be unsubstituted or substituted with1-3 independently selected halogen substituents; and wherein R³ isselected from phenyl or pyridinyl, each of which may be unsubstituted orsubstituted with 1-3 independently selected halogen substituents.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl or monocyclic heteroaryl; each of which may beunsubstituted or substituted with 1-3 substituents independentlyselected from halogen, cyano, and C1-C4 alkyl; wherein R³ is Ar²;wherein monocyclic heteroaryl is pyridinyl, pyrimidinyl, pyridazinyl orpyrazinyl; and wherein all other variables are as defined herein.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl, which may be unsubstituted or substituted with1-3 substituents independently selected from halogen, cyano and C1-C4alkyl; and wherein R³ is phenyl, which may be unsubstituted orsubstituted at the phenyl moiety with 1-3 independently selected halogensubstituents; or pyridinyl, which may be unsubstituted or substitutedwith 1-3 substituents independently selected from halogen, C1-C4 alkyl,C1-C4 alkyoxy, and mono- or di-C1-C4-alkylamino.

In a further aspect, the compound has a structure represented by aformula:

wherein Ar¹ is phenyl, which may be unsubstituted or substituted with1-3 independently selected halogen substituents; and wherein R³ isphenyl or pyridinyl, each of which may be unsubstituted or substitutedwith 1-3 independently selected halogen substituents.

Suitable substituents are described below.

a. Optional Covalent Bond

In various aspects, ----- is an optional covalent bond, wherein valenceis satisfied.

In a further aspect, ----- is present as a covalent bond, therebyjoining A¹ and A² with a covalent double bond. In a further aspect,----- is present, and A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.

In a further aspect, ----- is present, and R³ is selected from hydrogen,C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl;C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar².

In a further aspect, ----- is not present, thereby joining A¹ and A²with a covalent single bond. In a further aspect, ----- is not present,and A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b)and R^(1c) are independently selected from hydrogen, fluoro, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2a) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl;

In a further aspect, ----- is not present, and R³ is Ar²;

b. A Groups

In one aspect, when ----- is present, A¹ and A² are joined by a covalentdouble bond, A¹ is CR^(1a) and A² is CR^(2a). Thus, in a further aspect,the portion of the compound comprising A¹ and A² can have a structurerepresented by a formula:

In one aspect, when ----- is not present, A¹ and A² are joined by acovalent single bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c).Thus, in a further aspect, the portion of the compound comprising A¹ andA² can have a structure represented by a formula:

c. Ar¹ Groups

In one aspect, Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl.

In a further aspect, Ar¹ is unsubstituted. In a still further aspect,Ar¹ has 1, 2, or 3 substituents. In a yet further aspect, Ar¹ is phenyl.In an even further aspect, Ar¹ is phenyl with 1-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.

In a further aspect, Ar¹ is heteroaryl. In a still further aspect, Ar¹is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In a yet furtheraspect, Ar¹ is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl and has1-3 substituents independently selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.

In a further aspect, Ar¹ is substituted with 1-3 groups independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a yet further aspect, Ar¹ issubstituted with 1-3 groups selected from halogen, cyano, C1-C4 alkyl,and C1-C4 alkyloxy. In an even further aspect, Ar¹ is substituted with1-3 groups selected from halogen, methyl, trifluoromethyl, ethyl,propyl, and butyl. In a further aspect, Ar¹ is substituted with 1-3groups selected from methoxy, trifluoromethoxy, ethoxy, propyloxy, orbutyloxy. In a still further aspect, Ar¹ is substituted with 1-3 cyanogroups. In a yet further aspect, Ar¹ is substituted with 1-3 groupsselected from halogen, cyano, methyl, and trifluoromethyl.

In a further aspect, Ar¹ is substituted with 0-3 halogens. In a stillfurther aspect, Ar¹ is substituted with 1-3 halogens.

d. Ar²Groups

In one aspect, Ar² is phenyl or benzyl or —(C2-C6)-phenyl, andsubstituted with 0-3 substituents independently selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl).

In a further aspect, Ar² is unsubstituted. In a still further aspect,Ar² has 1, 2, or 3 substituents.

In a further aspect, Ar² is phenyl. In an even further aspect, Ar² isphenyl with 1-3 substituents independently selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl. In a still further aspect, Ar² is phenyl with 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl).

In a further aspect, Ar² is benzyl. In a yet further aspect, Ar² isbenzyl with 1-3 substituents independently selected from halogen, cyano,C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl. In a still further aspect, Ar² is benzyl with 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl).

In a further aspect, Ar² is —(C2-C6)-phenyl. In a yet further aspect,Ar² is —(C2-C6)-phenyl with 1-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl. In a still further aspect, Ar² is —(C2-C6)-phenylwith 1-3 substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl).

In a further aspect, Ar² is heteroaryl. In a still further aspect, Ar²is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In a yet furtheraspect, Ar² is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl and has1-3 substituents independently selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. Ina still further aspect, Ar² is pyridinyl, pyridazinyl, pyrimidinyl, orpyrazinyl and has 1-3 substituents independently selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl).

In a still further aspect, Ar² is pyridinyl. In a yet further aspect,Ar² is pyridinyl and has 1-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl. In a still further aspect, Ar² is pyridinyl and has1-3 substituents independently selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl).

In a further aspect, Ar² is pyridazinyl. In a yet further aspect, Ar² ispyridazinyl and has 1-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl. In a still further aspect, Ar² is pyridazinyl andhas 1-3 substituents independently selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl).

In a further aspect, Ar² is pyrimidinyl. In a yet further aspect, Ar² ispyrimidinyl and has 1-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl. In a still further aspect, Ar² is pyrimidinyl andhas 1-3 substituents independently selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl).

In a further aspect, Ar² is pyrazinyl. In a yet further aspect, Ar² ispyrazinyl and has 1-3 substituents independently selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl. In a still further aspect, Ar² is pyrazinyl and has 1-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl).

In a further aspect, Ar² is substituted with 1-3 groups independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a yet further aspect, Ar² issubstituted with 1-3 groups selected from halogen, cyano, C1-C4 alkyl,and C1-C4 alkyloxy. In an even further aspect, Ar² is substituted with1-3 groups selected from halogen, methyl, trifluoromethyl, ethyl,propyl, and butyl. In a further aspect, Ar² is substituted with 1-3groups selected from methoxy, trifluoromethoxy, ethoxy, propyloxy, orbutyloxy. In a still further aspect, Ar² is substituted with 1-3 groupsselected from methyl, fluoro, trifluoromethyl, methoxy, and —N(CH₃)₂.

In a further aspect, Ar² is substituted with 0-3 halogens. In a stillfurther aspect, Ar² is substituted with 1-3 halogens. In a yet furtheraspect, Ar² is substituted with 0-3 fluoro groups. In an even furtheraspect, Ar² is substituted with 1-3 fluoro groups.

e. R^(1a)Groups

In one aspect, when ----- is present, R^(1a) is selected from hydrogen,halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. In afurther aspect, R^(1a), when present, is hydrogen. In a yet furtheraspect, R^(1a), when present, is selected from hydrogen and halogen. Inan even further aspect, R^(1a), when present, is selected from hydrogen,fluoro, and chloro. In a still further aspect, R^(1a), when present, isselected from hydrogen, fluoro, iodo and chloro. In a still furtheraspect, R^(1a), when present, is selected from hydrogen, fluoro, andiodo.

In a further aspect, R^(1a), when present, is C1-C4 alkyl. In a stillfurther aspect, R^(1a), when present, is selected from hydrogen,halogen, methyl, trifluoromethyl, ethyl, propyl, and butyl. In a yetfurther aspect, R^(1a), when present, is selected from hydrogen, fluoro,chloro, methyl, trifluoromethyl, ethyl, propyl, and butyl. In an evenfurther aspect, R^(1a), when present, is selected from hydrogen, fluoro,methyl, trifluoromethyl, ethyl, propyl, and butyl. In a still furtheraspect, R^(1a), when present, is selected from hydrogen, fluoro, chloro,iodo, methyl, trifluoromethyl, ethyl, propyl, and butyl. In an evenfurther aspect, R^(1a), when present, is selected from hydrogen, fluoro,iodo, methyl, trifluoromethyl, ethyl, propyl, and butyl.

In further aspect, R^(1a), when present, is selected from hydrogen,methyl, trifluoromethyl, ethyl, propyl, and butyl. In a still furtheraspect, R^(1a), when present, is selected methyl, trifluoromethyl,ethyl, propyl, and butyl.

In a further aspect, R^(1a), when present, is selected halogen, methyl,trifluoromethyl, ethyl, propyl, and butyl. In a yet further aspect,R^(1a), when present, is selected from fluoro, chloro, methyl,trifluoromethyl, ethyl, propyl, and butyl. In an even further aspect,R^(1a), when present, is selected from fluoro, methyl, trifluoromethyl,ethyl, propyl, and butyl. In a still further aspect, R^(1a), whenpresent, is selected from fluoro, chloro, iodo, methyl, trifluoromethyl,ethyl, propyl, and butyl. In an even further aspect, R^(1a), whenpresent, is selected from fluoro, iodo, methyl, trifluoromethyl, ethyl,propyl, and butyl.

In a further aspect, R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkyl. In a stillfurther aspect, R^(1a) and R^(2a) are directly covalently bonded tocomprise, together with the intermediate atoms, a 3-, 4-, 5-, 6-, or7-membered fused cycloalkyl. In a yet further aspect, R^(1a) and R^(2a)are directly covalently bonded to comprise, together with theintermediate atoms, a substituted 3-, 4-, 5-, 6-, or 7-membered fusedcycloalkyl. In an even further aspect, R^(1a) and R^(2a) are directlycovalently bonded to comprise, together with the intermediate atoms, asubstituted 3-, 4-, 5-, 6-, or 7-membered fused cycloalkyl, and thefused cycloalkyl is substituted with 1 or 2 groups selected from methyl,ethyl, and propyl.

In a further aspect, R^(1a) and R^(2a) are not directly covalentlybonded. In a yet further aspect, R^(1a) and R^(2a), when present, areeach hydrogen. In a still further aspect, R^(1a) and R^(2a), whenpresent, are each methyl. In an even further aspect, of R^(1a) andR^(2a), when present, are independently selected from each hydrogen,methyl, and trifluoromethyl.

f. R^(1b) and R^(1c) Groups

In one aspect, when ----- is not present, each of R^(1b) and R^(1c) areindependently selected from hydrogen, fluoro, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl. In a stillfurther aspect, R^(1b) and R^(1c) when present, are each hydrogen. In ayet further aspect, R^(1b) and R^(1c), when present, are each C1-C4alkyl. In an even further aspect, each of R^(1b) and R^(1c) whenpresent, are independently selected from hydrogen and C1-C4 alkyl.

In a further aspect, each of R^(1b) and R^(1c) when present, areindependently selected from hydrogen and fluoro. In a yet furtheraspect, each of R^(1b) and R^(1c) when present, are independentlyselected from fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl. In an even further aspect, each of R^(1b) and R^(1c) whenpresent, are independently selected hydrogen fluoro, methyl,trifluoromethyl, ethyl, propyl, and butyl.

In a further aspect, R^(1b) and R^(1c) when present, are independentlyselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl. In a still further aspect, R^(1b) and R^(1c) whenpresent, are independently selected from hydrogen, methyl,trifluoromethyl, ethyl, propyl, and butyl.

In a further aspect, R^(1b) and R^(2b), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkyl. In a stillfurther aspect, R^(1b) and R^(1c) are covalently bonded and, togetherwith the intermediate carbon, comprise a 3- to 7-memberedspirocycloalkyl. In a yet further aspect, R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate carbon, comprise asubstituted 3- to 7-membered spirocycloalkyl. In an even further aspect,R^(1b) and R^(1c) are covalently bonded and, together with theintermediate carbon, comprise a substituted 3- to 7-memberedspirocycloalkyl, and the spirocycloalkyl is substituted with 1 or 2groups selected from methyl, ethyl, and propyl.

g. R^(2a) Groups

In one aspect, when ----- is present, R^(2a) is selected from hydrogen,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. In a furtheraspect, R^(2a), when present, is hydrogen. In a yet further aspect,R^(2a), when present, is methyl. In an even further aspect, R^(2a), whenpresent, is C1-C4 alkyl. In a further aspect, R^(2a), when present, isselected from methyl, trifluoromethyl, ethyl, propyl, and butyl. In astill further aspect, R^(2a), when present, is selected from hydrogenand methyl.

h. R^(2b) and R^(2c) Groups

In one aspect, when ----- is not present, each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl. In a further aspect, each of R^(2b)and R^(2c), when present, are each hydrogen. In a still further aspect,each of R^(2b) and R^(2c), when present, are each C1-C4 alkyl.

In a further aspect, each of R^(2b) and R^(2c), when present, areindependently selected from hydrogen and C1-C4 alkyl. In a yet furtheraspect, each of R^(2b) and R^(2c), when present, are independentlyselected from hydrogen, methyl, trifluoromethyl, ethyl, propyl, andbutyl. In a still further aspect, wherein each of R^(2b) and R^(2c),when present, are independently selected from hydrogen, methyl, andtrifluoromethyl. In an even further aspect, wherein each of R^(2b) andR^(2c), when present, are independently selected from hydrogen andmethyl.

In a further aspect, R^(2b) and R^(2c) are covalently bonded and,together with the intermediate carbon, comprise a 3- to 7-memberedspirocycloalkyl. In a still further aspect, R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate carbon, comprise asubstituted 3- to 7-membered spirocycloalkyl. In a yet further aspect,R^(2b) and R^(2c) are covalently bonded and, together with theintermediate carbon, comprise a substituted 3- to 7-memberedspirocycloalkyl, and the spirocycloalkyl is substituted with 1 or 2groups selected from methyl, ethyl, and propyl.

i. R³ Groups

In one aspect, R³, when ----- is present, is selected from hydrogen,C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl;C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar².

In one aspect, R³, when ----- is not present, is Ar².

In a further aspect, R³, when ----- is present, is hydrogen. In a stillfurther aspect, R³, when ----- is present, is selected from hydrogen andC1-C6 alkyl. In an even further aspect, R³, when ----- is present, isselected from methyl, trifluoromethyl, ethyl, propyl, butyl, pentyl, andhexyl.

In a further aspect, R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; and (C3-C8 heterocycloalkyl)-C1-C6 alkyl-. Ina still further aspect, R³, when ----- is present, is selected fromhydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl,isobutyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl,3,3-dimethylbutan-2-yl, 2,3-dimethylbutan-2-yl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I,—CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂Br, —CH₂CH₂I, —(CH₂)₂CH₂F, —(CH₂)₂CH₂Cl,—(CH₂)₂CH₂Br, —(CH₂)₂CH₂I, —CHF₂, —CF₃, —CHCl₂, —CCl₃, —CHBr₂, —CBr₃,—CHI₂, —Cl₃, —CH₂CHF₂, —CH₂CF₃, —CH₂CHCl₂, —CH₂CCl₃, —CH₂CHBr₂,—CH₂CBr₃, —CH₂CHI₂, —CH₂Cl₃, —(CH₂)₂CHF₂, —(CH₂)₂CF₃, —(CH₂)₂CHCl₂,—(CH₂)₂CCl₃, —(CH₂)₂CHBr₂, —(CH₂)₂CBr₃, —(CH₂)₂CHI₂, —(CH₂)₂Cl₃, —OCH₃,—OCH₂CH₃, —O(CH₂)₂CH₃, —OCH(CH₃)₂, and —OCH(CH₂CH₃)(CH₃). In a yetfurther aspect, R³, when ----- is present, is selected from hydrogen,methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CF₃, —CHCl₂, —CCl₃,—CHBr₂, —CBr₃, —CHI₂, —Cl₃, and —OCH₃. In a yet further aspect,hydrogen, methyl, cyclopropyl, cyclopropylmethyl, —CH₂F, —CH₂Cl, —CH₂Br,—CH₂I, —CF₃, —CHCl₂, —CCl₃, —CHBr₂, —CBr₃, —CHI₂, —Cl₃, and —OCH₃. In aneven further aspect, hydrogen, methyl, cyclopropyl, cyclopropylmethyl,—CH₂F, —CHF₂, —CF₃, and —OCH₃.

In a further aspect, R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C3-C8 cycloalkyl; and (C3-C8 cycloalkyl)-C1-C6alkyl-. In a still further aspect, R³, when ----- is present, isselected from hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl,sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl,3,3-dimethylbutan-2-yl, 2,3-dimethylbutan-2-yl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, and cyclohexylmethyl. In a yet further aspect, R³,when is present, is selected from hydrogen, methyl, ethyl, propyl,isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, andcyclohexylmethyl. In an even further aspect, R³, when ----- is present,is selected from hydrogen, methyl, cyclopropyl, and cyclopropylmethyl.In a still further aspect, R³, when ----- is present, is selected frommethyl, cyclopropyl, and cyclopropylmethyl. In a yet further aspect, R³,when ----- is present, is selected from hydrogen, cyclopropyl, andcyclopropylmethyl. In an even further aspect, R³, when ----- is present,is selected from cyclopropyl and cyclopropylmethyl. In a still furtheraspect, R³, when ----- is present, is cyclopropyl. In a yet furtheraspect, R³, when ----- is present, is cyclopropylmethyl.

In a further aspect, R³, when ----- is present, is phenyl. In a stillfurther aspect, R³, when ----- is present, is phenyl with 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a yet further aspect,R³, when ----- is present, is monocyclic heteroaryl. In an even furtheraspect, R³, when ----- is present, is pyridinyl, pyridazinyl,pyrimidinyl, or pyrazinyl. In a further aspect, R³, when ----- ispresent, is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; with 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.

In a further aspect, R³, when ----- is not present, is phenyl. In astill further aspect, R³, when ----- is not present, is phenyl with 1-3substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a yet further aspect,R³, when ----- is not present, is monocyclic heteroaryl. In an evenfurther aspect, R³, when ----- is not present, is pyridinyl,pyridazinyl, pyrimidinyl, or pyrazinyl. In a further aspect, R³, when----- is not present, is pyridinyl, pyridazinyl, pyrimidinyl, orpyrazinyl; with 1-3 substituents selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.

In a further aspect, R³ is phenyl. In a still further aspect, R³ isphenyl with 1-3 substituents selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl. In a yetfurther aspect, R³ is monocyclic heteroaryl. In an even further aspect,R³ is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In a furtheraspect, R³ is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; with1-3 substituents selected from halogen, cyano, C1-C4 alkyl, C1-C4alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.

j. R⁴ Groups

In one aspect, R⁴ is selected from hydrogen, halogen, cyano, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy. In a further aspect, R⁴ is hydrogen. Ina yet further aspect, R⁴ is selected from hydrogen and C1-C4 alkyl. In astill further aspect, R⁴ is C1-C4 alkoxy.

In a further aspect, R⁴ is selected from halogen, cyano, and C1-C4alkyl. In a still further aspect, wherein R⁴ is selected from C1-C4alkylamino and C1-C4 dialkylamino. In a yet further aspect, R⁴ isselected from C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.

In a further aspect, R⁴ is selected from hydrogen and halogen. In a yetfurther aspect, R⁴ is selected from hydrogen, fluoro, chloro, and iodo.In a still further aspect, R⁴ is selected from hydrogen, fluoro, chloro,and bromo. In an even further aspect, In a yet further aspect, R⁴ isselected from hydrogen, bromo, and iodo.

k. R^(5a) and R^(5b) Groups

In one aspect, each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. Ina further aspect, R^(5a) and R^(5b) are both hydrogen. In a stillfurther aspect, one of R^(5a) and R^(5b) is hydrogen and the other isC1-C4 alkyl.

l. R⁶ GROUPS

In one aspect, R⁶ is C1-C4 alkyl. In a further aspect, R⁶ is selectedfrom methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, andtert-butyl. In a yet further aspect, R⁶ is selected from methyl, ethyl,propyl, and isopropyl. In a still further aspect, R⁶ is selected frommethyl and ethyl. In an even further aspect, R⁶ is methyl. In a stillfurther aspect, R⁶ is ethyl.

m. R⁷ Groups

In one aspect, R⁷ is selected from hydrogen and C1-C4 alkyl. In afurther aspect, R⁷ is hydrogen. In a still further aspect, R⁷ isselected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, and tert-butyl. In a yet further aspect, R⁷ isselected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a stillfurther aspect, R⁷ is selected from hydrogen, methyl and ethyl. In aneven further aspect, R⁷ is hydrogen and methyl. In a still furtheraspect, R⁷ is hydrogen and ethyl.

In a further aspect, R⁷ is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In a yet furtheraspect, R⁷ is selected from methyl, ethyl, propyl, and isopropyl. In astill further aspect, R⁷ is selected from methyl and ethyl. In an evenfurther aspect, R⁷ is methyl. In a still further aspect, R⁷ is ethyl.

In a further aspect, each of R⁷ and R⁸ is hydrogen. In a still furtheraspect, R⁷ is hydrogen and R⁸ is methyl. In a yet further aspect, R⁷ ishydrogen and R⁸ is ethyl. In an even further aspect, R⁷ is methyl and R⁸is ethyl.

n. R⁸ Groups

In one aspect, R⁸ is selected from hydrogen and C1-C4 alkyl. In afurther aspect, R⁸ is hydrogen. In a still further aspect, R⁸ isselected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, and tert-butyl. In a yet further aspect, R⁸ isselected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a stillfurther aspect, R⁸ is selected from hydrogen, methyl and ethyl. In aneven further aspect, R⁸ is hydrogen and methyl. In a still furtheraspect, R⁸ is hydrogen and ethyl.

In a further aspect, R⁸ is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In a yet furtheraspect, R⁸ is selected from methyl, ethyl, propyl, and isopropyl. In astill further aspect, R⁸ is selected from methyl and ethyl. In an evenfurther aspect, R⁸ is methyl. In a still further aspect, R⁸ is ethyl.

o. R⁹ Groups

In one aspect, R⁹ is selected from halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In various further aspects, R⁹is selected from C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl. In a further aspect, R⁹ is hydrogen.

In one aspect, R⁹ is selected from halogen and C1-C4 alkyl. In a stillfurther aspect, R⁹ is selected from halogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In a yet furtheraspect, R⁹ is selected from halogen, methyl, ethyl, propyl, andisopropyl. In a still further aspect, R⁹ is selected from halogen,methyl and ethyl. In an even further aspect, R⁹ is halogen and methyl.In a still further aspect, R⁹ is halogen and ethyl.

In a further aspect, R⁹ is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In a yet furtheraspect, R⁹ is selected from methyl, ethyl, propyl, and isopropyl. In astill further aspect, R⁹ is selected from methyl and ethyl. In an evenfurther aspect, R⁹ is methyl. In a still further aspect, R⁹ is ethyl.

In a further aspect, R⁹ is selected from —Cl, —Br, and —I. In a yetfurther aspect, R⁹ is —Cl. In a still further aspect, R⁹ is —Br. In aneven further aspect, R⁹ is —I.

In a further aspect, R⁹ is halogen, methyl, ethyl, —CH₂F, —CH₂Cl,—CH₂Br, —CH₂I, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂Br, —CH₂CH₂I, —CHF₂, —CF₃,—CHCl₂, —CCl₃, —CHBr₂, —CBr₃, —CHI₂, —Cl₃, —CH₂CHF₂, —CH₂CF₃, —CH₂CHCl₂,—CH₂CCl₃, —CH₂CHBr₂, —CH₂CBr₃, —CH₂CHI₂, and —CH₂Cl₃. In a still furtheraspect, R⁹ is halogen, methyl, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHF₂,—CF₃, —CHCl₂, —CCl₃, —CHBr₂, —CBr₃, —CHI₂, and —O₃.

p. Halogen (X)

In one aspect, halogen is fluoro, chloro, bromo or iodo. In a stillfurther aspect, halogen is fluoro, chloro, or bromo. In a yet furtheraspect, halogen is fluoro or chloro. In a further aspect, halogen isfluoro. In an even further aspect, halogen is chloro or bromo. In aneven further aspect, halogen is chloro. In a yet further aspect, halogenis iodo. In a still further aspect, halogen is bromo.

It is also contemplated that pseudohalogens (e.g. triflate, mesylate,brosylate, etc.) can be used as leaving groups in place of halogens incertain aspects.

2. Example Compounds

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In a further aspect, a compound can be present as:

In yet a further aspect, the compound produced exhibits positiveallosteric modulation of mGluR5 response to glutamate as a increase inresponse to non-maximal concentrations of glutamate in human embryonickidney cells transfected with rat mGluR5 in the presence of thecompound, compared to the response to glutamate in the absence of thecompound. In a further aspect, human embryonic kidney cells aretransfected with human mGluR5. In yet a further aspect, human embryonickidney cells are transfected with mammalian mGluR5. In yet a furtheraspect, the compound produced exhibits positive allosteric modulation ofmGluR5 after contacting a cell expressing mGluR5.

In a further aspect, the disclosed compounds are allosteric modulatorsof mGluR5, in particular, positive allosteric modulators of mGluR5. Thediclosed compounds can potentiate glutamate responses by binding to anallosteric site other than the glutamate orthosteric binding site. Theresponse of mGluR5 to a concentration of glutamate is increased when thedisclosed compounds are present. In a further aspect, the disclosedcompounds can have their effect substantially at mGluR5 by virtue oftheir ability to enhance the function of the receptor.

It is contemplated that one or more compounds can optionally be omittedfrom the disclosed invention.

3. Positive Allosteric Modulation of mGLuR5 Response

Generally, the disclosed compounds exhibit potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith mGluR5 in the presence of the compound, compared to the response toglutamate in the absence of the compound. For example, a compound canexhibit positive allosteric modulation of mGluR5 with an EC₅₀ of lessthan about 10,000 nM, of less than about 5,000 nM. of less than about1,000 nM, of less than about 500 nM, or of less than about 100 nM. In afurther aspect, the mGluR5 is rat mGluR5. In a still further aspect, themGluR5 is human mGluR5.

In one aspect, the disclosed compounds exhibit potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith human mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound. In a furtheraspect, the transfected cell line is the H10H cell line. In a yetfurther aspect, the transfected cell line is the H12H cell line. Forexample, a compound can exhibit positive allosteric modulation oftransfected human mGluR5 ith an EC₅₀ of less than about 10,000 nM, ofless than about 5,000 nM. of less than about 1,000 nM, of less thanabout 500 nM, or of less than about 100 nM.

In one aspect, the disclosed compounds exhibit potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith rat mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound. For example, acompound can exhibit positive allosteric modulation of transfected ratmGluR5 with an EC₅₀ of less than about 10,000 nM, of less than about5,000 nM. of less than about 1,000 nM, of less than about 500 nM, or ofless than about 100 nM.

C. METABOTROPIC GLUTAMATE RECEPTOR ACTIVITY

The utility of the compounds in accordance with the present invention aspotentiators of metabotropic glutamate receptor activity, in particularmGluR5 activity, can be demonstrated by methodology known in the art.Human embryonic kidney (HEK) cells transfected with rat mGluR5 wereplated in clear bottom assay plates for assay in a Functional DrugScreening System (FDSS). In the alternative assay, HEK cells transfectedwith human mGluR5 were plated for assay in the FDSS. In some cases theHEK cells transfected with human mGluR5 were the H10H cell line.Alternatively, the HEK cells transfected with human mGluR5 were the H12Hcell line. Rat assay results were found to correlate well with humanassay results. The cells were loaded with a Ca²⁺-sensitive fluorescentdye (e.g., Fluo-4), and the plates were washed and placed in the FDSSinstrument. After establishment of a fluorescence baseline for twelveseconds, the compounds of the present invention were added to the cells,and the response in cells was measured. Five minutes later, an mGluR5agonist (e.g., glutamate, 3,5-dihydroxyphenylglycine, or quisqualate)was added to the cells, and the response of the cells was measured.Potentiation of the agonist response of mGluR5 by the compounds in thepresent invention was observed as an increase in response to non-maximalconcentrations of agonist (here, glutamate) in the presence of compoundcompared to the response to agonist in the absence of compound.

The above described assay operated in two modes. In the first mode, arange of concentrations of the present compounds were added to cells,followed by a single fixed concentration of agonist. If a compound actedas a potentiator, an EC₅₀ value for potentiation and a maximum extent ofpotentiation by the compound at this concentration of agonist wasdetermined by non-linear curve fitting. In the second mode, severalfixed concentrations of the present compounds were added to variouswells on a plate, followed by a range of concentrations of agonist foreach concentration of present compound; the EC₅₀ values for the agonistat each concentration of compound were determined by non-linear curvefitting. A decrease in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a leftward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5potentiation at a given concentration of the present compound. Anincrease in the EC₅₀ value of the agonist with increasing concentrationsof the present compounds (a rightward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5antagonism at a given concentration of the present compound. The secondmode also indicates whether the present compounds also affect themaximum response to mGluR5 to agonists.

In one aspect, the disclosed compounds exhibit potentiation of mGluR5response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith a mammalian mGluR5 in the presence of the compound, compared to theresponse to glutamate in the absence of the compound. For example, humanembryonic kidney cells can be transfected with human mGluR5. Forexample, human embryonic kidney cells can be transfected with ratmGluR5. For example, a compound can exhibit positive allostericmodulation of mGluR5 (e.g., rmGluR5) with an EC₅₀ of less than about10,000 nM, of less than about 5,000 nM. of less than about 1,000 nM, ofless than about 500 nM, or of less than about 100 nM. Alternatively, thedisclosed compounds exhibit potentiation of mGluR5 response to glutamateas an increase in response to non-maximal concentrations of glutamate inhuman embryonic kidney cells transfected with human mGluR5 in thepresence of the compound, compared to the response to glutamate in theabsence of the compound. In a further aspect, the transfected cell lineis the H10H cell line. In a yet further aspect, the transfected cellline is the H12H cell line. For example, a compound can exhibit positiveallosteric modulation of mGluR5 (e.g., hmGluR5) with an EC₅₀ of lessthan about 10,000 nM, of less than about 5,000 nM. of less than about1,000 nM, of less than about 500 nM, or of less than about 100 nM.

In particular, the disclosed compounds exhibit activity in potentiatingthe mGluR5 receptor in the aforementioned assays, generally with an EC₅₀for potentiation of less than about 10 μM. Preferred compounds withinthe present invention had activity in potentiating the mGluR5 receptorwith an EC₅₀ for potentiation of less than about 500 nM. Preferredcompounds further caused a leftward shift of the agonist EC₅₀ by greaterthan 3-fold. These compounds did not cause mGluR5 to respond in theabsence of agonist, and they did not elicit a significant increase inthe maximal response of mGluR5 to agonists. These compounds areselective positive allosteric modulators (potentiators) of human and ratmGluR5 compared to the other seven subtypes of metabotropic glutamatereceptors.

In vivo efficacy for disclosed compounds can be measured in a number ofpreclinical rat behavioral model where known, clinically usefulantipsychotics display similar positive responses. For example,disclosed compounds can reverse amphetamine-induced hyperlocomotion inmale Sprague-Dawley rats at doses ranging from 1 to 100 mg/kg p.o.

D. METHODS OF MAKING THE COMPOUNDS

In one aspect, the invention relates to methods of making compoundsuseful as positive allosteric modulators of the metabotropic glutamatereceptor subtype 5 (mGluR5), which can be useful in the treatmentneurological and psychiatric disorders associated with glutamatedysfunction and other diseases in which metabotropic glutamate receptorsare involved.

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, inaddition to other standard manipulations known in the literature or toone skilled in the art. The following examples are provided so that theinvention might be more fully understood, are illustrative only, andshould not be construed as limiting.

In one aspect, the disclosed compounds comprise the products of thesynthetic methods described herein. In a further aspect, the disclosedcompounds comprise a compound produced by a synthetic method describedherein. In a still further aspect, the invention comprises apharmaceutical composition comprising a therapeutically effective amountof the product of the disclosed methods and a pharmaceuticallyacceptable carrier. In a still further aspect, the invention comprises amethod for manufacturing a medicament comprising combining at least onecompound of any of disclosed compounds or at least one product of thedisclosed methods with a pharmaceutically acceptable carrier or diluent.

In a further aspect, the compound produced exhibits potentiation ofmGluR5 response to glutamate as an increase in response to non-maximalconcentrations of glutamate in human embryonic kidney cells transfectedwith mGluR5 in the presence of the compound, compared to the response toglutamate in the absence of the compound.

1. Route I

In one aspect, substituted imidazo[1,2-c]pyrimidin-5(6H)-one analogs ofthe present invention can be prepared generically as shown below.

Compounds are represented in generic form, with sub stituents as notedin compound descriptions elsewhere herein. A more specific example isset forth below.

In one aspect, compounds of type 1.2 can be prepared by hydrogenation ofthe corresponding unsaturated analog as represented by compound 1.1.Briefly, reaction comprising compound 1.1 and hydrogen gas is performedin the presence of a suitable catalyst, e.g. palladium hydroxide orRaney nickel, and an inert solvent such as methanol, ethanol or amixture of methanol and N,N-dimethylformamide. Typically the reaction isperformed at about 30° C. to about 70° C., with a hydrogen gas pressureof about normal atmospheric pressure to about 50 psi or at about 30° C.to about 100° C. with a continuous flow of hydrogen gas, for a period oftime sufficient to complete the reaction.

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein Ar¹ is phenyl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclic heteroarylsubstituted with 0-3 substituents independently selected from halo,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) isselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein R³ is selected from phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ ismonocyclic heteroaryl substituted with 0-3 substituents independentlyselected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R⁴ is selected fromhydrogen, halogen, cyano, and C1-C4 alkyl; wherein each of R^(5a) andR^(5b) is independently selected from hydrogen and C1-C4 alkyl; whereinR^(1a) and R^(2a) are optionally covalently bonded and, together withthe intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkyl, and (b) hydrogenating the compound, therebyyielding a compound having a structure represented by a formula:

In a further aspect, hydrogenating comprises reaction with hydrogen inthe presence of a palladium catalyst. In a yet further aspect,hydrogenating comprises reaction with hydrogen in the presence of Raneynickel.

2. Route II

In one aspect, substituted imidazo[1,2-c]pyrimidin-5(6H)-one analogs ofthe present invention can be prepared generically by one of thesynthetic schemes as shown below.

Compounds are represented in generic form, with sub stituents as notedin compound descriptions elsewhere herein. More specific examples areset forth below.

In one aspect, compounds of type 1.1 can be prepared from compounds oftype 2.1 by reaction with a suitable, aryl halide or heteroaryl halide,wherein the halo moiety is bromo, chloro or iodo, in the presence of acoupling agent, e.g. copper(I)iodide or palladium (II) acetate, aligand, e.g. N,N-dimethylethylenediamine or2-dicyclohexylphosphino-2′,4′,6′-triiso-propyl-1,1′-biphenyl, and abase, e.g. potassium carbonate or cesium carbonate. Reactions of thistype are typically carried out in an inert solvent such as toluene or1,4-dioxane at an appropriate reaction temperature, e.g. from about 100°C. to about 140° C., for a period of time sufficient to complete thereaction.

In one aspect, compounds of type 1.1 can alternatively be prepared fromcompounds of type 2.3 by reaction with a suitable aryl alcohol in thepresence of a suitable base, e.g. potassium carbonate, in an inertsolvent such as acetonitrile. Reactions of this type are typicallycarried out at an appropriate reaction temperature, e.g. from about 60°C. to about 100° C., for a period of time sufficient to insurecompletion of the reaction.

In one aspect, compounds of type 1.2 can be prepared from compounds oftype 2.2 by reaction with a suitable, aryl halide or heteroaryl halide,wherein the halo moiety is bromo, chloro or iodo, in the presence of acoupling agent, e.g. copper(I)iodide or palladium (II) acetate, aligand, e.g. N,N-dimethylethylenediamine or2-dicyclohexylphosphino-2′,4′,6′-triiso-propyl-1,1′-biphenyl, and abase, e.g. potassium carbonate or cesium carbonate. Reactions of thistype are typically carried out in an inert solvent such as toluene or1,4-dioxane at an appropriate reaction temperature, e.g. from about 100°C. to about 140° C., for a period of time sufficient to complete thereaction.

In one aspect, compounds of type 1.2 can alternatively be prepared fromcompounds of type 2.4 by reaction with a suitable aryl alcohol in thepresence of a suitable base, e.g. potassium carbonate, in an inertsolvent such as acetonitrile. Reactions of this type are typicallycarried out at an appropriate reaction temperature, e.g. from about 60°C. to about 100° C., for a period of time sufficient to insurecompletion of the reaction.

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R⁴ is selected from hydrogen, halogen, cyano, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, and (b) reacting the compound with R³X, whereinX is a leaving group, and wherein R³, when ----- is present, is selectedfrom hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; thereby substitutingat the amide. In a further aspect, X is a halogen.

In a further aspect, the prepared compound has a structure representedby a formula:

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when is present and A¹ and A² are joined by acovalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R⁴ is selected from hydrogen, halogen, cyano, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, and (b) coupling the compound with R³X, in thepresence of a coupling reagent, wherein X is bromo or iodo, and whereinR³, when ----- is present, is selected from hydrogen, C1-C6 alkyl; C1-C6alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl;C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; thereby substituting at the amide. In a further aspect,the coupling reagent is copper(I)iodide.

In a further aspect, the prepared compound has a structure representedby a formula:

In a further aspect, the compound provided has a structure representedby a formula:

In a still further aspect, the compound formed when the above compoundis the compound provided has a structure represented by a formula:

In a yet further aspect, the method further comprises hydrogenating thecompound formed, thereby yielding a compound having a structurerepresented by a formula:

In an even further aspect, hydrogenating comprises reaction withhydrogen in the presence of a palladium catalyst. In a further aspect,hydrogenating comprises reaction with hydrogen in the presence of Raneynickel.

In a further aspect, the compound provided has a structure representedby a formula:

In a still further aspect, the compound formed when the above compoundis the compound provided has a structure represented by a formula:

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein X is a leaving group; wherein ----- is an optional covalentbond, wherein valence is satisfied; wherein when ----- is present and A¹and A² are joined by a covalent double bond, A¹ is CR^(1a), and A² isCR^(2a); wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selectedfrom hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is not present and A¹ and A² arejoined by a covalent single bond, A¹ is CR^(1b)R^(1c), and A² isCR^(2b)R^(2c); wherein each of R^(1b) and R^(1c) are independentlyselected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl, or R^(1b) and R^(1c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein R^(1a) and R^(2a), whenpresent, are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkenyl; wherein R^(1b) and R^(2b), when present, areoptionally covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered fused cycloalkyl;wherein R³, when ----- is present, is selected from hydrogen, C1-C6alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-;(C3-C8 heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; whereinAr² is phenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, and (b) reacting the compound with Ar¹OH,wherein Ar¹ is phenyl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclic heteroarylsubstituted with 0-3 substituents independently selected from halo,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl, thereby forming:

In a further aspect, the leaving group is a halogen. In a still furtheraspect, the halogen is chloro. In a yet further aspect, the reaction isperformed in the presence of base.

In a further aspect, the compound provided has a structure representedby the formula:

In a still further aspect, the compound formed when the above compoundis the compound provided has a structure represented by a formula:

In a yet further aspect, the method further comprises hydrogenating thecompound formed, thereby yielding a compound having a structurerepresented by a formula:

In an even further aspect, hydrogenating comprises reaction withhydrogen in the presence of a palladium catalyst. In a further aspect,hydrogenating comprises reaction with hydrogen in the presence of Raneynickel.

In a further aspect, the compound provided has a structure representedby the formula:

In a still further aspect, the compound formed when the above compoundis the compound provided has a structure represented by a formula:

3. Route III

In one aspect, substituted imidazo[1,2-c]pyrimidin-5(6H)-one analogs ofthe present invention can be prepared generically as shown below.

Compounds are represented in generic form, with sub stituents as notedin compound descriptions elsewhere herein. More specific examples areset forth below.

In one aspect, compounds of type 1.1 can be prepared starting with4-aminopyrimidin-2(1H)-one analogs shown as compound type 3.1. Compoundtype 3.1 is reacted with a suitable alkylating compound with anappropriate leaving group, such as R³Br (although leaving groups otherthan bromo can also be utilized). The reaction is carried out in thepresence of a suitable base, e.g. tetra-N-butylammonium hydroxide, in aninert solvent such as N,N-dimethylformamide at a suitable temperature,e.g. from about 0° C. to about 40° C., for a period of time sufficientto complete the reaction. Similar procedures are described in Eur. J.Med. Chem. (2009) 44:1172-1179. The product of this reaction, compound3.2, is then reacted with a suitable dihaloketone, e.g.1,2-dichloroacetone, in the presence of an inert solvent, e.g.N,N-dimethylformamide, to afford a compound of type 2.3. This reactioncan be carried out by heating with microwave irradiation for a period oftime sufficient to insure completion. Conversion of the product,compound 2.3, to a compound of type 1.1 is accomplished by methodsdescribed above for Route II. Briefly, the compound is reacted with asuitable aryl alcohol in the presence of a suitable base, e.g. potassiumcarbonate, in an inert solvent such as acetonitrile. Reactions of thistype are typically carried out at an appropriate reaction temperature,e.g. from about 60° C. to about 100° C., for a period of time sufficientto insure completion of the reaction.

In one aspect, compounds of type 1.3 can be prepared starting with4-aminopyrimidin-2(1H)-one analogs shown as compound type 3.1. Compoundtype 3.1 is reacted with an appropriate aryl (including heteroaryl)boronic derivative represented by the formula Ar²B(OH)₂ in the presenceof a suitable coupling agent, e.g. copper(II)acetate monohydrate and asuitable ligand, e.g. N,N,N′,N′-tetramethylethylenediamine. The reactionis carried out in an inert solvent such as toluene at a suitabletemperature, e.g. from about 0° C. to about 40° C. for a period of timesufficient to insure completion of the reaction. Procedures similar tothose described in Eur. J. Org. Chem. (2005) 5154-5157 can be used. Theproduct of this reaction, compound 3.3, is then reacted with a suitabledihaloketone, e.g. 1,2-dichloroacetone, in the presence of an inertsolvent, e.g. N,N-dimethylformamide, to afford a compound of type 2.5.This reaction can be carried out by heating with microwave irradiationfor a period of time sufficient to insure completion. Conversion of theproduct, compound 2.5, to a compound of type 1.3 is accomplished bymethods described above for Route II. Briefly, the compound is reactedwith a suitable aryl alcohol in the presence of a suitable base, e.g.potassium carbonate, in an inert solvent such as acetonitrile. Reactionsof this type are typically carried out at an appropriate reactiontemperature, e.g. from about 60° C. to about 100° C., for a period oftime sufficient to insure completion of the reaction.

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, (b) reacting the compound with a compound represented by theformula:

wherein R⁴ is selected from hydrogen, halogen, cyano, and C1-C4 alkyl;and wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen and C1-C4 alkyl. In a still further aspect, reacting is carriedout using microwave irradiation.

In various aspects, the compound represented by the formula:

R⁴ is hydrogen or C1-C4 alkyl. In a further aspect, R⁴ is hydrogen. In astill further aspect, R⁴ is hydrogen, methyl, ethyl, propyl orisopropyl. In a yet further aspect, R⁴ is hydrogen or methyl.

In a further aspect, the prepared compound has a structure representedby a formula:

In a further aspect, the method further comprises the step of reactingthe compound formed with Ar¹OH, wherein Ar¹ is phenyl substituted with0-3 substituents independently selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orAr¹ is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, thereby forming a compoundrepresented by a formula:

In a still further aspect, reacting the compound formed with Ar¹OH isperformed in the presence of base. In a yet further aspect, the methodfurther comprises hydrogenating the compound formed following reactionwith Ar¹OH, thereby yielding a compound having a structure representedby a formula:

4. Route IV

In one aspect, substituted imidazo[1,2-c]pyrimidin-5(6H)-one analogs ofthe present invention can be prepared generically as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 1.1 and 1.2 can be prepared startingwith a suitable 6-chloro-2-(methylthio)pyrimidin-4-amine analog, such ascompound type 4.1, and reacting with a suitable dihaloketone, e.g.1,2-dichloroacetone. The reaction is carried out in an appropriate inertsolvent, e.g. N,N-dimethylformamide, at a convenient reactiontemperature, e.g. from about 20° C. to about 70° C., for a period oftime to insure completion of the reaction. Similar procedures to thosedescribed in patent application number PCT/EP2008/001682 (Publicationnumber WO/2008/113469) can be used. Appropriate6-chloro-2-(methylthio)pyrimidin-4-amine analogs can be purchasedcommercially. The product can be reacted with a suitable aryl alcohol toafford compounds of type 4.3 using procedures described above for RouteII. Briefly, the reaction can be performed in the presence of a suitablebase, e.g. potassium carbonate, in an inert solvent such asacetonitrile. Reactions of this type are typically carried out at anappropriate reaction temperature, e.g. from about 20° C. to about 100°C., for a period of time sufficient to insure completion of thereaction. The product of this reaction can be converted to a compound oftype 4.4 by hydrolysis in the presence of lithium hydroxide. Thereaction is carried out in an appropriate inert solvent, e.g.tetrahydrofuran and water, at a convenient and suitable temperature, e.gfrom about 30° C. to about 70° C., for a period of time to insurecompletion of the reaction. A compound of type 2.1 is prepared from theproduct by a hydrogenation reaction in the presence of hydrogen gas anda suitable catalyst, e.g. palladium hydroxide. The reaction is carriedout in an inert solvent, e.g. methanol, at a convenient and suitabletemperature, e.g. from about 30° C. to about 80° C., under a suitablehydrogen pressure, e.g. from about atmospheric pressure to about 50 psi,for a period of time to insure completion of the reaction. The reactionsteps and condition leading from compound of type 2.1 to compound type1.1, and then from compound type 1.1 to compound 1.2 are as describedabove for Routes I and II.

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, and (b) reacting the compoundwith a compound represented by a formula:

wherein R⁴ is selected from hydrogen, halogen, cyano, and C1-C4 alkyl;and wherein each of R^(5a) and R^(5b) is independently selected fromselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl.

In a further aspect, the prepared compound has a structure representedby a formula:

In a further aspect, the method further comprises the step of reactingthe compound formed with Ar¹OH, wherein Ar¹ is phenyl substituted with0-3 substituents independently selected from halogen, cyano, C1-C4alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orAr¹ is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, thereby forming a compoundrepresented by a formula:

In a yet further aspect, the reaction is performed in the presence ofbase. In a still further aspect, the method further comprises the stepof hydrolysis on the compound formed from reaction with Ar¹OH, whereinhydrolysis is performed in the presence of lithium hydroxide, therebyforming a compound represented by a formula:

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein Ar¹ is phenyl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclic heteroarylsubstituted with 0-3 substituents independently selected from halo,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, (b) hydrogenating the compound to yield acompound represented by the formula:

In a yet further aspect, hydrogenation is carried out with hydrogen inthe presence of a palladium catalyst. In a still further aspect, thepalladium catalyst is palladium hydroxide.

In a further aspect, the method further comprises the step of couplingthe compound formed with R³X, in the presence of a coupling reagent,wherein X is bromo or iodo; wherein R³, is selected from hydrogen, C1-C6alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-;(C3-C8 heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; whereinAr² is phenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and thereby substituting at the amide. In a yet further aspect, thecoupling reagent is copper(I)iodide. In an even further aspect, theamide formed has a structure represented by a formula:

In a further aspect, the method further comprises the step of reactingthe compound formed with R³X, wherein X is a leaving group; wherein R³,is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);thereby substituting at the amide. In an even further aspect, X is ahalogen. In a still further aspect, the amide formed has a structurerepresented by a formula:

5. Route V

In one aspect, substituted imidazo[1,2-c]pyrimidin-5(6H)-one analogs ofthe present invention can be prepared generically as shown below.

Compounds are represented in generic form, with sub stituents as notedin compound descriptions elsewhere herein. More specific examples areset forth below.

In one aspect, compounds of type 5.1 can be prepared from the analogouscompound of type 1.1 by reaction with an appropriate N-halosuccinimide,e.g. N-chlorosuccinimide, in an inert solvent, e.g.N,N-dimethylformamide. The reaction is carried out at an appropriatetemperature, e.g. from about 120° C. to about 150° C., for a period oftime sufficient to insure completion of the reaction.

In one aspect, compounds of type 5.1 can alternatively be preparedstarting with a compound of type 2.3. The reaction for the first step iscarried out by reacting compound 2.3 with a suitable N-halosuccinimide,e.g. N-bromosuccinimide, in the presence of benzoyl peroxide in anappropriate inert solvent, e.g. 1,2-dichloroethane. The reaction iscarried out at an appropriate temperature, e.g. from about roomtemperature to about 60° C., for a period of time to insure completionof the reaction to afford compound type 5.2. The conversion of compoundtype 5.2 to compound type 5.1 is carried out using reaction conditionsas described above for Route II.

The halogenated compound type 5.1 can be converted to a number ofderivatives, including the corresponding alkoxy (compound type 5.3),alkylamine (compound type 5.4), and alkyl (compound type 5.5). Thetypical reaction conditions for preparing each derivative areillustrated in the reaction schemes above.

In one aspect, compounds of type 5.6 can be prepared from the analogouscompound of type 1.2 by reaction with an appropriate N-halosuccinimide,e.g. N-chlorosuccinimide, N-iodosuccinimide or N-bromosuccinimide, in aninert solvent, e.g. N,N-dimethylformamide, mixture of acetonitrile andacetic acid or in the presence of benzoyl peroxide in1,2-dichloroethane. The reaction is carried out at an appropriatetemperature, e.g. at room temperature or by heating with microwaveirradiation, for a period of time sufficient to insure completion of thereaction.

The halogenated compound type 5.6 can be converted to a number ofderivatives, including the corresponding alkoxy (compound type 5.7),alkylamine (compound type 5.8), and alkyl (compound type 5.9). Thetypical reaction conditions for preparing each derivative areillustrated in the reaction schemes above.

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein when ----- is present and A¹ and A² are joined by a covalentdouble bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a) isselected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl;C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) halogenating the compound by reaction with N-halosuccinimide. In ayet further aspect, halogenating is reaction with N-bromosuccinimide. Ina still further aspect, halogenating is reaction withN-chlorosuccinimide.

In a further aspect, the halogenated compound formed has a structurerepresented by a formula:

In a further aspect, the method further comprises the step of reactingthe halogenated compound formed with Ar¹OH, wherein Ar¹ is phenylsubstituted with 0-3 substituents independently selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl, or Ar¹ is monocyclic heteroaryl substituted with 0-3substituents independently selected from halo, cyano, C1-C4 alkyl, C1-C4alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, thereby forminga compound represented by a formula:

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein Ar¹ is phenyl substituted with 0-3 substituents independentlyselected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclic heteroarylsubstituted with 0-3 substituents independently selected from halo,cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6alkyloxy; C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl;C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) halogenating the compound by reaction with N-halosuccinimide. In astill further aspect, halogenating is reacting with N-bromosuccinimide.In a yet further aspect, halogenating is reacting withN-chlorosuccinimide.

In a further aspect, the halogenated compound has a structurerepresented by a formula:

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein X is halogen; wherein Ar¹ is phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl, or Ar¹ ismonocyclic heteroaryl substituted with 0-3 substituents independentlyselected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when ----- is presentand A¹ and A² are joined by a covalent double bond, A¹ is CR^(1a), andA² is CR^(2a); wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) isselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is not present and A¹ and A² arejoined by a covalent single bond, A¹ is CR^(1b)R^(1c), and A² isCR^(2b)R^(2c); wherein each of R^(1b) and R^(1c) are independentlyselected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl, or R^(1b) and R^(1c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein R^(1a) and R^(2a), whenpresent, are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkenyl; wherein R^(1b) and R^(2b), when present, areoptionally covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered fused cycloalkyl;wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) reacting the compound with R⁶OH in the presence of a metal catalyst,wherein R⁶ is C1-C4 alkyl, thereby forming,

In a further aspect, the metal catalyst comprises palladium, copper, orboth. In a still further aspect, the metal catalyst is copper(I)iodide.In a yet further aspect, X is chloro or bromo.

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein X is halogen; wherein Ar¹ is phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ ismonocyclic heteroaryl substituted with 0-3 substituents independentlyselected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when ----- is presentand A¹ and A² are joined by a covalent double bond, A¹ is CR^(1a), andA² is CR^(2a); wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) isselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is not present and A¹ and A² arejoined by a covalent single bond, A¹ is CR^(1b)R^(1c), and A² isCR^(2b)R^(2c); wherein each of R^(1b) and R^(1c) are independentlyselected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl, or R^(1b) and R^(1c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein R^(1a) and R^(2a), whenpresent, are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkenyl; wherein R^(1b) and R^(2b), when present, areoptionally covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered fused cycloalkyl;wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) reacting the compound with NR⁷R⁸ in the presence of a metalcatalyst, wherein each of R⁷ and R⁷ are independently selected from Hand C1-C4 alkyl, thereby forming,

In a further aspect, X is chloro or bromo. In a yet further aspect, themetal catalyst comprises a palladium compound. In an even furtheraspect, the metal catalyst comprises a palladium compound which istris(dibenzylideneacetone)dipalladium(0). In a further aspect, the metalcatalyst comprises a palladium compound which istris(dibenzylideneacetone)dipalladium(0):2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl:sodiumtert-butoxide.

Thus, in one aspect, the invention relates to a method of making acompound comprising the steps of: (a) providing a compound having astructure represented by a formula:

wherein X is halogen; wherein Ar¹ is phenyl substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ ismonocyclic heteroaryl substituted with 0-3 substituents independentlyselected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when ----- is presentand A¹ and A² are joined by a covalent double bond, A¹ is CR^(1a), andA² is CR^(2a); wherein R^(1a) is selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) isselected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is not present and A¹ and A² arejoined by a covalent single bond, A¹ is CR^(1b)R^(1c), and A² isCR^(2b)R^(2c); wherein each of R^(1b) and R^(1c) are independentlyselected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl, or R^(1b) and R^(1c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein each of R^(2b) and R^(2c) areindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) are covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered spirocycloalkyl; wherein R^(1a) and R^(2a), whenpresent, are optionally covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedfused cycloalkenyl; wherein R^(1b) and R^(2b), when present, areoptionally covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered fused cycloalkyl;wherein R³ is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and(b) reacting the compound with R⁹B(OH)₂ in the presence of a metalcatalyst, wherein R⁹ is selected from C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl thereby forming,

In a further aspect, X is bromo or chloro. In a yet further aspect, themetal catalyst comprises a palladium or copper compound. In a stillfurther aspect, the metal catalyst comprisestris(dibenzylideneacetone)dipalladium(0). In an even further aspect, themetal catalyst comprises tetrakis(triphenylphosphine)palladium(0). In afurther aspect, the copper compound is present as copper(I)iodide.

6. Route VI

In one aspect, substituted imidazo[1,2-c]pyrimidin-5(6H)-one analogs ofthe present invention can be prepared generically as shown below.

Compounds are represented in generic form, with sub stituents as notedin compound descriptions elsewhere herein. More specific examples areset forth below.

In one aspect, compounds of type 6.6 can be prepared starting with4-aminopyrimidin-2(1H)-one analogs shown as compound type 6.1. Compoundof type 6.1 is reacted with a suitable alkylating compound with anappropriate leaving group, such as R³Br (although leaving groups otherthan bromo can also be utilized). The reaction is carried out in thepresence of a suitable base, e.g. tetra-N-butylammonium hydroxide, in aninert solvent such as N,N-dimethylformamide at a suitable temperature,e.g. from about 0° C. to about 40° C., for a period of time sufficientto complete the reaction. Similar procedures are described in Eur. J.Med. Chem. (2009) 44:1172-1179. The product of this reaction, compound6.2, is then reacted with sodium metaperiodate in the presence of iodinein an appropriate mixture of inert solvents, e.g. acetic acid, water andsulfuric acid, at a convenient reaction temperature, e.g. from about 60°C. to about 100° C., for a period of time sufficient to complete thereaction. The compound of type 6.3 is then reacted with a suitabledihaloketone, e.g. 1,2-dichloroacetone, in the presence of an inertsolvent, e.g. N,N-dimethylformamide, to afford a compound of type 6.4.This reaction can be carried out by heating with microwave irradiationfor a period of time sufficient to insure completion. Conversion of theproduct, compound 6.4, to a compound of type 6.5 is accomplished bymethods described above for Route II. Briefly, the compound is reactedwith a suitable aryl alcohol in the presence of a suitable base, e.g.potassium carbonate, in an inert solvent such as acetonitrile. Reactionsof this type are typically carried out at an appropriate reactiontemperature, e.g. from about 60° C. to about 100° C., for a period oftime sufficient to insure completion of the reaction. The compound oftype 6.5 is then reacted with methylboronic acid in the presence of anappropriate coupling agent, e.g.tetrakis(triphenylphosphine)palladium(0) and a base, e.g. potassiumcarbonate. Reactions of this type are typically carried out in asuitable mixture of inert solvents, e.g. 1,4-dioxane andN,N-dimethylformamide. This reaction can be carried out by heating withmicrowave irradiation for a period of time sufficient to insurecompletion.

In one aspect, compounds of type 6.11 can be prepared starting with4-aminopyrimidin-2(1H)-one analogs shown as compound type 6.1. Compoundtype 6.1 is reacted with an appropriate aryl (including heteroaryl)boronic derivative represented by the formula Ar²B(OH)₂ in the presenceof a suitable coupling agent, e.g. copper(II)acetate monohydrate and asuitable ligand, e.g. N,N,N′N′-tetramethylethylenediamine. The reactionis carried out in an inert solvent such as toluene at a suitabletemperature, e.g. from about 0° C. to about 40° C. for a period of timesufficient to insure completion of the reaction. Procedures similar tothose described in Eur. J. Org. Chem. (2005) 5154-5157 can be used. Theproduct of this reaction, compound 6.7, is then reacted with sodiummetaperiodate in the presence of iodine in an appropriate mixture ofinert solvents, e.g. acetic acid, water and sulfuric acid, at aconvenient reaction temperature, e.g. from about 60° C. to about 100°C., for a period of time sufficient to complete the reaction. Thecompound of type 6.8 is then reacted with a suitable dihaloketone, e.g.1,2-dichloroacetone, in the presence of an inert solvent, e.g.N,N-dimethylformamide, to afford a compound of type 6.9. This reactioncan be carried out by heating with microwave irradiation for a period oftime sufficient to insure completion. Conversion of the product,compound 6.9, to a compound of type 6.10 is accomplished by methodsdescribed above for Route II. Briefly, the compound is reacted with asuitable aryl alcohol in the presence of a suitable base, e.g. potassiumcarbonate, in an inert solvent such as acetonitrile. Reactions of thistype are typically carried out at an appropriate reaction temperature,e.g. from about 60° C. to about 100° C., for a period of time sufficientto insure completion of the reaction. The compound of type 6.10 is thenreacted with methylboronic acid in the presence of an appropriatecoupling agent, e.g., tetrakis(triphenylphosphine)palladium(0) and abase, e.g. potassium carbonate. Reactions of this type are typicallycarried out in a suitable mixture of inert solvents, e.g. 1,4-dioxaneand N,N-dimethylformamide. This reaction can be carried out by heatingwith microwave irradiation for a period of time sufficient to insurecompletion.

In a further aspect, the compound produced exhibits positive allostericmodulation of mGluR5 response to glutamate as an increase in response tonon-maximal concentrations of glutamate in human embryonic kidney cellstransfected with rat mGluR5 in the presence of the compound, compared tothe response to glutamate in the absence of the compound. In a furtheraspect, human embryonic kidney cells are transfected with human mGluR5.In yet a further aspect, human embryonic kidney cells are transfectedwith mammalian mGluR5.

In a further aspect, the compound produced exhibits positive allostericmodulation of mGluR5 (e.g., rmGluR5) with an EC₅₀ of less than about10,000 nM, of less than about 5,000 nM. of less than about 1,000 nM, ofless than about 500 nM, or of less than about 100 nM. In a still furtheraspect, the compound produced exhibits potentiation of mGluR5 responseto glutamate as an increase in response to non-maximal concentrations ofglutamate in human embryonic kidney cells transfected with human mGluR5in the presence of the compound, compared to the response to glutamatein the absence of the compound. In a further aspect, the transfectedcell line is the H10H cell line. In a still further aspect, thetransfected cell line is the H12H cell line. In a yet further aspect,the compound produced exhibits positive allosteric modulation of mGluR5(e.g., hmGluR5) with an EC₅₀ of less than about 10,000 nM, of less thanabout 5,000 nM. of less than about 1,000 nM, of less than about 500 nM,or of less than about 100 nM.

In particular, the compound produced exhibits activity in potentiatingthe mGluR5 receptor in the disclosed assays, generally with an EC₅₀ forpotentiation of less than about 10 μM. Preferred compounds within thepresent invention had activity in potentiating the mGluR5 receptor withan EC₅₀ for potentiation of less than about 500 nM. Preferred compoundsfurther caused a leftward shift of the agonist EC₅₀ by greater than3-fold. These compounds did not cause mGluR5 to respond in the absenceof agonist, and they did not elicit a significant increase in themaximal response of mGluR5 to agonists. These compounds are selectivepositive allosteric modulators (potentiators) of human and rat mGluR5compared to the other seven subtypes of metabotropic glutamatereceptors.

It is contemplated that each disclosed methods can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed methods can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

Table I below lists specific compounds, preferred synthetic route(s),and characterization data. Table II below lists specific compounds withexperimentally determined mGluR5 activity determined in a cell-basedassay. The mGluR5 activity was determined using the metabotropicglutamate receptor activity assays in human embryonic kidney cells asdescribed herein, wherein the human embryonic kidney cells weretransfected with human mGluR5. The compounds in Table I were synthesizedwith methods identical or analogous to those shown herein. The SyntheticRoute Reference indicated in Table I refers to the Reaction Schemenumber described above. The requisite starting materials werecommercially available, described in the literature, or readilysynthesized by one skilled in the art of organic synthesis.

TABLE I Synthetic Route Parent No. Structure Reference MW M + H 1

IV 241.1 242 2

II, III 255.1 256 3

II, III 335.1 336 4

II, III 335.1 336 5

II, III 353.1 354 6

II, III 353.1 354 7

II, III 331.1 332 8

II, IV 332.1 333 9

II, IV 336.1 337 10

II, IV 350.1 351 11

II, IV 332.1 333 12

II, III 349.1 350 13

II, III 360.1 361 14

II, III 353.1 354 15

II, IV 332.1 333 16

II, III 403.1 404 17

II, III 295.1 296 18

II, III 336.1 337 19

II, III 336.1 337 20

II, III 353.1 354 21

II, III 419.1 420 22

II, III 410.1 411 23

II, IV 350.1 351 24

II, IV 361.1 362 25

II, IV 349.1 350 26

VI 461.0 462 27

VI 349.1 350 28

II, III 349.1 350 29

V 369.1 370 30

V 413.0 414 31

I 337.1 338 32

I 337.1 338 33

I 355.1 356 34

I 355.1 356 35

I 355.1 356 36

I 334.1 335 37

I 351.1 352 38

I 352.1 353 39

I 338.1 339 40

I 352.1 353 41

V 463.0 464 42

V 371.1 372 43

V 415.0 416 44

V 351.1 352

TABLE II EC₅₀ No. Structure (nM) pEC₅₀ E_(max)(%) 1

>30,200 <4.52 19 2

>10,000 <5 69 3

392 6.57 79 4

525 6.29 68 5

228 6.67 79 6

224 6.67 73 7

1,245 5.9 80 8

2,291 5.66 43 9

490 6.31 75 10

292 6.5 70 11

1,318 5.94 59 12

468 6.29 33 13

350 6.46 40 14

302 6.51 72 15

8,318 <5 51 16

1,288 5.93 50 17

1,096 5.98 51 18

2,512 5.67 66 19

>30,200 <4.52 59 20

78 7.07 73 21

>10,000 <5 — 22

>10,000 <5 — 23

327 6.48 60 24

201 6.68 64 25

570 6.24 46 26

n.d. n.d. n.d. 27

>30,200 <4.52 16 28

1862 5.83 49 29

>30,200 <4.52 17 30

n.d. n.d. n.d. 31

97 6.99 71 32

226 6.61 70 33

97 6.99 75 34

65 7.17 73 35

188 6.77 68 36

468 6.33 63 37

191 6.69 48 38

166 6.75 72 39

389 6.50 64 40

351 6.57 61 41

n.d. n.d. n.d. 42

>30,200 <4.52 17 43

n.d. n.d. n.d. 44

>30,200 <4.52 20 “n.d.” means not determined

E. PHARMACEUTICAL COMPOSITIONS

In one aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds. That is, a pharmaceuticalcomposition can be provided comprising a therapeutically effectiveamount of at least one disclosed compound or at least one product of adisclosed method and a pharmaceutically acceptable carrier.

In certain aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases oracids. When the compound of the present invention is acidic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic bases and organic bases.Salts derived from such inorganic bases include aluminum, ammonium,calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium,manganese (-ic and -ous), potassium, sodium, zinc and the like salts.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acids”,includes inorganic acids, organic acids, and salts prepared therefrom,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, and/or pharmaceutically acceptable salt(s) thereof, can alsobe administered by controlled release means and/or delivery devices. Thecompositions can be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention can include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the compounds of the invention. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In the treatment conditions which require negative allosteric modulationof metabotropic glutamate receptor activity an appropriate dosage levelwill generally be about 0.01 to 500 mg per kg patient body weight perday and can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably 0.5 to 100 mg/kg per day. A suitable dosage level can beabout 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, orabout 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the from of tabletscontaining 1.0 to 1000 miligrams of the active ingredient, particularly1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500,600, 750, 800, 900 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage of the patient to be treated. Thecompound can be administered on a regimen of 1 to 4 times per day,preferably once or twice per day. This dosing regimen can be adjusted toprovide the optimal therapeutic response.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Such factorsinclude the age, body weight, general health, sex, and diet of thepatient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of theparticular disease undergoing therapy.

The present invention is further directed to a method for themanufacture of a medicament for modulating glutamate receptor activity(e.g., treatment of one or more neurological and/or psychiatric disorderassociated with glutamate dysfunction) in mammals (e.g., humans)comprising combining one or more disclosed compounds, products, orcompositions with a pharmaceutically acceptable carrier or diluent.Thus, in one aspect, the invention relates to a method for manufacturinga medicament comprising combining at least one disclosed compound or atleast one disclosed product with a pharmaceutically acceptable carrieror diluent.

The disclosed pharmaceutical compositions can further comprise othertherapeutically active compounds, which are usually applied in thetreatment of the above mentioned pathological conditions.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

F. METHODS OF USING THE COMPOUNDS AND COMPOSITIONS

The amino acid L-glutamate (referred to herein simply as glutamate) isthe principal excitatory neurotransmitter in the mammalian centralnervous system (CNS). Within the CNS, glutamate plays a key role insynaptic plasticity (e.g., long term potentiation (the basis of learningand memory)), motor control and sensory perception. It is now wellunderstood that a variety of neurological and psychiatric disorders,including, but not limited to, schizophrenia general psychosis andcognitive deficits, are associated with dysfunctions in theglutamatergic system. Thus, modulation of the glutamatergic system is animportant therapeutic goal. Glutamate acts through two distinctreceptors: ionotropic and metabotropic glutamate receptors. The firstclass, the ionotropic glutamate receptors, is comprised of multi-subunitligand-gated ion channels that mediate excitatory post-synapticcurrents. Three subtypes of ionotropic glutamate receptors have beenidentified, and despite glutamate serving as agonist for all threereceptor subtypes, selective ligands have been discovered that activateeach subtype. The ionotropic glutamate receptors are named after theirrespective selective ligands: kainite receptors, AMPA receptors and NMDAreceptors.

The second class of glutamate receptor, termed metabotropic glutamatereceptors, (mGluRs), are G-protein coupled receptors (GPCRs) thatmodulate neurotransmitter release or the strength of synaptictransmission, based on their location (pre-or post-synaptic). The mGluRsare family C GPCR, characterized by a large (˜560 amino acid) “venus flytrap” agonist binding domain in the amino-terminal domain of thereceptor. This unique agonist binding domain distinguishes family CGPCRs from family A and B GPCRs wherein the agonist binding domains arelocated within the 7-strand transmembrane spanning (7TM) region orwithin the extracellular loops that connect the strands to this region.To date, eight distinct mGluRs have been identified, cloned andsequenced. Based on structural similarity, primary coupling tointracellular signaling pathways and pharmacology, the mGluRs have beenassigned to three groups: Group I (mGluR1 and mGluR5), Group II (mGluR2and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8). Group ImGluRs are coupled through Gαq/11 to increase inositol phosphate andmetabolism and resultant increases in intracellular calcium. Group ImGluRs are primarily located post-synaptically and have a modualtoryeffect on ion channel activity and neuronal excitability. Group II(mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8)mGluRs are primarily located pre-synaptically where they regulate therelease of neurotransmitters, such as glutamate. Group II and Group IIImGluRs are coupled to Gαi and its associated effectors such as adenylatecyclase.

Post-synaptic mGluRs are known to functionally interact withpost-synaptic ionotropic glutamate receptors, such as the NMDA receptor.For example, activation of mGluR5 by a selective agonist has been shownto increase post-synaptic NMDA currents (Mannaioni et. al. J. Neurosci.21:5925-5934 (2001)). Therefore, modulation of mGluRs is an approach tomodulating glutamatergic transmission. Numerous reports indicate thatmGluR5 plays a role in a number of disease states including anxiety(Spooren et. al. J. Pharmacol. Exp. Therapeut. 295:1267-1275 (2000),Tatarczynska et al. Br. J. Pharmaol. 132:1423-1430 (2001)),schizophrenia (reviewed in Chavez-Noriega et al. Curr. Drug Targets: CNS& Neurological Disorders 1:261-281 (2002), Kinney, G. G. et al. J.Pharmacol. Exp. Therapeut. 313:199-206 (2005)), addiction to cocaine(Chiamulera et al. Nature Neurosci. 4:873-874 (2001), Parkinson'sdisease (Awad et al. J. Neurosci. 20:7871-7879 (2000), Ossowska et al.Neuropharmacol. 41: 413-420 (2001), and pain (Salt and Binns Neurosci.100:375-380 (2001).

Phencyclidine (PCP) and other NMDA receptor antagonists induce apsychotic state in humans similar to schizophrenia. In schizophreniapatients, PCP and ketamine exacerbate/precipitate preexisting positiveand negative symptoms in stable patients. Treatment with NMDA receptorco-agonists can improve positive and negative symptoms. A schematic ofthe NMDA receptor is shown in FIG. 1. Activation of mGluR5 potentiatesNMDA receptor function as shown in FIG. 2. Orthosteric ligands lacksubtype selectivity and can cause unwanted side effects. Allostericmodulators (see FIG. 3) that can target transmembrane domains offer apharmacologically attractive alternative. In one aspect, transmembranedomains can be significantly less conserved than extracellular loopregions.

The compounds disclosed herein are allosteric modulators of metabotropicglutamate receptors, in particular they are positive allostericmodulators of mGluR5. Without wishing to be bound by a particulartheory, the The compounds disclosed herein are allosteric modulators ofmetabotropic glutamate receptors, in particular they are positiveallosteric modulators of mGluR5. Again, without wishing to be bound by aparticular theory, the compounds disclosed herein do not appear to bindto the glutamate recognition site, the orthosteric ligand site, butinstead to an allosteric site. In the presence of glutamate or anagonist of mGluR5, the compounds of this invention increase the mGluR5response. The compounds disclosed herein are expected to have theireffect at mGluR5 by virtue of their ability to increase the response ofsuch receptors to glutamate or mGluR5 agonists, enhancing the responseof the receptor.

Hence, the present invention relates compounds disclosed herein for useas a medicament, as well as to the use of a compound disclosed herein ora pharmaceutical composition according to the invention for themanufacture of a medicament, including, for example, the manufacture ofa medicament for treating or preventing, in particular treating, acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect ofallosteric modulators of mGluR5, e.g. positive allosteric modulatorsthereof. The present invention also relates to a compound disclosedherein or a pharmaceutical composition according to the invention foruse in the treatment or prevention of a condition in a subject such as amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of allostericmodulators of mGluR5, e.g. positive allosteric modulators thereof.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with glutamatedysfunction. In various aspects, the compounds disclosed herein areuseful for treating, preventing, ameliorating, controlling or reducingthe risk of a variety of neurological and psychiatric disordersassociated with glutamate dysfunction, in a subject such as a mammal,including a human, the treatment or prevention of which is affected orfacilitated by the neuromodulatory effect of allosteric modulators ofmGluR5, e.g. particular positive allosteric modulators thereof. Thepresent invention also relates to the use of a compound disclosed hereinor a pharmaceutical composition according to the invention for themanufacture of a medicament for treating, preventing, ameliorating,controlling or reducing the risk of various neurological and psychiatricdisorders associated with glutamate dysfunction in a subject such as amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of allostericmodulators of mGluR5, e.g. positive allosteric modulators thereof.

Examples of disorders associated with glutamate dysfunction include:autism, acute and chronic neurological and psychiatric disorders such ascerebral deficits subsequent to cardiac bypass surgery and grafting,stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia(including AIDS-induced dementia), Alzheimer's disease, Huntington'sChorea, amyotrophic lateral sclerosis, ocular damage, retinopathy,cognitive disorders, idiopathic and drug-induced Parkinson's disease,muscular spasms and disorders associated with muscular spasticityincluding tremors, epilepsy, convulsions, migraine (including migraineheadache), urinary incontinence, substance tolerance, addictivebehavior, including addiction to substances (including opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.), withdrawal from such addictive substances(including substances such as opiates, nicotine, tobacco products,alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), obesity,psychosis, schizophrenia, anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder), mooddisorders (including depression, mania, bipolar disorders), trigeminalneuralgia, hearing loss, tinnitus, macular degeneration of the eye,emesis, brain edema, pain (including acute and chronic pain states,severe pain, intractable pain, neuropathic pain, and post-traumaticpain), tardive dyskinesia, sleep disorders (including narcolepsy),attention deficit/hyperactivity disorder, and conduct disorder.

Epilepsy can be treated or prevented by the compositions disclosedherein, including absence epilepsy. In various aspects, the compositionsdisclosed herein can have a protective role for spike and wavedischarges associated with absence seizures. Metabotropic glutamate(mGlu) receptors positioned at synapses of the cortico-thalamo-corticalcircuitry that generates spike-and-wave discharges (SWDs) associatedwith absence seizures. Thus, without wishing to be bound by a particulartheory, mGluR receptors are therapeutic targets for the treatment ofabsence epilepsy (e.g. see Epilepsia, 52(7):1211-1222, 2011;Neuropharmacology 60 (2011) 1281e1291; and abstract from 7thInternational conference on metabotropic glutamate receptors, Oct. 2-6,2011 Taormina, Italy, “Pharmacological activation of metabotropicglutamate receptor subtype reduces Spike and Wave Discharges in theWAG/Rij rat model of absence epilepsy,” I. Santolini, V. D'Amore, C. M.van Rijn, A. Simonyi, A, Prete, P. J. Conn, C. Lindsley, S. Zhou, P. N.Vinson, A. L. Rodriguez, C. K. Jones, S. R. Stauffer, F. Nicoletti, G.van Luijtelaar and R. T. Ngomba).

Anxiety disorders that can be treated or prevented by the compositionsdisclosed herein include generalized anxiety disorder, panic disorder,and obsessive compulsive disorder. Addictive behaviors include addictionto substances (including opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal fromsuch addictive substances (including substances such as opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.) and substance tolerance.

Thus, in some aspects of the disclosed method, the disorder is dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, including positive and negative symptoms thereof andcognitive dysfunction related to schizophrenia, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, chorea, pain, migraine,diabetes, dystonia, obesity, eating disorders, brain edema, sleepdisorder, narcolepsy, anxiety, affective disorder, panic attacks,unipolar depression, bipolar disorder, and psychotic depression.

Thus, provided is a method for treating or preventing schizophrenia,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding schizophrenia and related disorders.

Also provided is a method for treating or prevention anxiety,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding anxiety and related disorders. These include: panic disorderwith or without agoraphobia, agoraphobia without history of panicdisorder, specific phobia, social phobia, obsessive-compulsive disorder,post-traumatic stress disorder, acute stress disorder, generalizedanxiety disorder, anxiety disorder due to a general medical condition,substance-induced anxiety disorder and anxiety disorder not otherwisespecified.

In various aspects, the condition or disease is a central nervous systemdisorder selected from the group of anxiety disorders, psychoticdisorders, personality disorders, substance-related disorders, eatingdisorders, mood disorders, migraine, epilepsy or convulsive disorders,childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia.

In a further aspect, the central nervous system disorder is an anxietydisorder, selected from the group of agoraphobia, generalized anxietydisorder (GAD), obsessive-compulsive disorder (OCD), panic disorder,posttraumatic stress disorder (PTSD), social phobia and other phobias.

In a further aspect, the central nervous system disorder is a psychoticdisorder selected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder

In a further aspect, the central nervous system disorder is apersonality disorder selected from the group of obsessive-compulsivepersonality disorder and schizoid, schizotypal disorder.

In a further aspect, the central nervous system disorder is asubstance-related disorder selected from the group of alcohol abuse,alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium,alcohol-induced psychotic disorder, amphetamine dependence, amphetaminewithdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence,nicotine withdrawal, opioid dependence and opioid withdrawal.

In a further aspect, the central nervous system disorder is an eatingdisorder selected from the group of anorexia nervosa and bulimianervosa.

In a further aspect, the central nervous system disorder is a mooddisorder selected from the group of bipolar disorders (I & II),cyclothymic disorder, depression, dysthymic disorder, major depressivedisorder and substance-induced mood disorder.

In a further aspect, the central nervous system disorder is migraine.

In a further aspect, the central nervous system disorder is epilepsy ora convulsive disorder selected from the group of generalizednonconvulsive epilepsy, generalized convulsive epilepsy, petit malstatus epilepticus, grand mal status epilepticus, partial epilepsy withor without impairment of consciousness, infantile spasms, epilepsypartialis continua, and other forms of epilepsy.

In a further aspect, the central nervous system disorder isattention-deficit/hyperactivity disorder.

In a further aspect, the central nervous system disorder is a cognitivedisorder selected from the group of delirium, substance-inducedpersisting delirium, dementia, dementia due to HIV disease, dementia dueto Huntington's disease, dementia due to Parkinson's disease, dementiaof the Alzheimer's type, substance-induced persisting dementia and mildcognitive impairment.

At present, the fourth edition of the Diagnostic & Statistical Manual ofMental Disorders (DSM-IV) of the American Psychiatric Associationprovides a diagnostic tool for the identification of the disordersdescribed herein. The person skilled in the art will recognize thatalternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders described herein exist, and thatthese evolve with medical and scientific progresses.

Therefore, the invention also relates to a disclosed compound, or apharmaceutically acceptable salt, including pharmaceutically acceptableacid or base addition salts, hydrate, solvate, polymorphy, orstereoisomeric form thereof, for use in the treatment of any one of thediseases mentioned hereinbefore.

In a further aspect, the invention also relates to a disclosed compound,or a pharmaceutically acceptable salt, including pharmaceuticallyacceptable acid or base addition salts, hydrate, solvate, polymorphy, orstereoisomeric form thereof, for the treatment or prevention, inparticular treatment, of any one of the diseases mentioned hereinbefore.

In a further aspect, the invention relates to relates to a disclosedcompound, or a pharmaceutically acceptable salt, includingpharmaceutically acceptable acid or base addition salts, hydrate,solvate, polymorphy, or stereoisomeric form thereof, for the manufactureof a medicament for the treatment or prevention of any one of thedisease conditions mentioned hereinbefore.

In a further aspect, the invention also relates to the use of relates toa disclosed compound, or a pharmaceutically acceptable salt, includingpharmaceutically acceptable acid or base addition salts, hydrate,solvate, polymorphy, or stereoisomeric form thereof, for the manufactureof a medicament for the treatment of any one of the disease conditionsmentioned hereinbefore.

In a further aspect, the invention relates to a disclosed compound, or apharmaceutically acceptable salt, including pharmaceutically acceptableacid or base addition salts, hydrate, solvate, polymorphy, orstereoisomeric form thereof, administered to mammals, e.g. humans, forthe treatment or prevention of any one of the diseases mentionedhereinbefore.

In a further aspect, relates to a method of treating warm-bloodedanimals, such as mammals including humans, suffering from any one of thediseases mentioned hereinbefore, and a method of preventing inwarm-blooded animals, such as mammals including humans, any one of thediseases mentioned hereinbefore by administering a disclosed compound,or a pharmaceutically acceptable salt, including pharmaceuticallyacceptable acid or base addition salts, hydrate, solvate, polymorphy, orstereoisomeric form thereof. Said methods comprise the administration,i.e. the systemic or topical administration, preferably oraladministration, of a therapeutically effective amount of a disclosedcompound, or a pharmaceutically acceptable salt, includingpharmaceutically acceptable acid or base addition salts, hydrate,solvate, polymorphy, or stereoisomeric form thereof, to warm-bloodedanimals, such as mammals including humans.

In various aspects, the invention also relates to a method for theprevention and/or treatment of any one of the diseases mentionedhereinbefore comprising administering a therapeutically effective amountof a disclosed compound, or a pharmaceutically acceptable salt,including pharmaceutically acceptable acid or base addition salts,hydrate, solvate, polymorphy, or stereoisomeric form thereof, to apatient in need thereof.

In various aspects, a disclosed compound is a positive allostericmodulators of mGluR5, and can enhance the response of mGluR5 toglutamate, thus it is an advantage that the present methods utilizeendogenous glutamate. In a further aspect, positive allostericmodulators of mGluR5, such as the disclosed compounds, enhance theresponse of mGluR5 to agonists, it is understood that the presentinvention extends to the treatment of neurological and psychiatricdisorders associated with glutamate dysfunction by administering aneffective amount of a disclosed compound, or a pharmaceuticallyacceptable salt, including pharmaceutically acceptable acid or baseaddition salts, hydrate, solvate, polymorphy, or stereoisomeric formthereof, in combination with an mGluR5 agonist.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for which adisclosed compound, or a pharmaceutically acceptable salt, includingpharmaceutically acceptable acid or base addition salts, hydrate,solvate, polymorphy, or stereoisomeric form thereof, or the other drugsmay have utility, where the combination of the drugs together are saferor more effective than either drug alone.

The disclosed compounds can be used as single agents or in combinationwith one or more other drugs in the treatment, prevention, control,amelioration or reduction of risk of the aforementioned diseases,disorders and conditions for which compounds of formula I or the otherdrugs have utility, where the combination of drugs together are safer ormore effective than either drug alone. The other drug(s) can beadministered by a route and in an amount commonly used therefore,contemporaneously or sequentially with a disclosed compound. When adisclosed compound is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchdrugs and the disclosed compound is preferred. However, the combinationtherapy can also be administered on overlapping schedules. It is alsoenvisioned that the combination of one or more active ingredients and adisclosed compound will be more efficacious than either as a singleagent.

In one aspect, the subject compounds can be coadministered withanti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, muscarinic agonists, muscarinic potentiatorsHMG-CoAreductase inhibitors, NSAIDs and anti-amyloid antibodies.

In another aspect, the subject compounds can be administered incombination with sedatives, hypnotics, anxiolytics, antipsychotics,selective serotonin reuptake inhibitors (SSRIs), monoamine oxidaseinhibitors (MAOIs), 5-HT2 antagonists, GlyT1 inhibitors and the likesuch as, but not limited to: risperidone, clozapine, haloperidol,fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and saltsthereof and combinations thereof.

In another aspect, the subject compound can be used in combination withlevodopa (with or without a selective extracerebral decarboxylaseinhibitor), anticholinergics such as biperiden, COMT inhibitors such asentacapone, A2a adenosine antagonists, cholinergic agonists, NMDAreceptor antagonists and dopamine agonists.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

a. Treatment of a Neurological and/or Psychiatric Disorder AssociatedWith Glutamate Dysfunction

In one aspect, the invention relates to a method for the treatment of adisorder associated with mGluR5 activity in a mammal comprising the stepof administering to the mammal at least one disclosed compound or atleast one disclosed product in a dosage and amount effective to treatthe disorder in the mammal. In a further aspect, the mammal is a human.In a further aspect, the mammal has been diagnosed with a need fortreatment of the disorder prior to the administering step. In a furtheraspect, the method further comprises the step of identifying a mammal inneed of treatment of the disorder.

In one aspect, the invention relates to a method for the treatment of aneurological and/or psychiatric disorder associated with glutamatedysfunction in a mammal comprising the step of administering to themammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In a further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 10,000 nM. In astill further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 5,000 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits positive allosteric modulation ofmGluR5 with an EC₅₀ of less than about 500 nM. In a yet further aspect,the compound exhibits positive allosteric modulation of mGluR5 with anEC₅₀ of less than about 100 nM.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior tothe administering step. In a further aspect, the method furthercomprises the step of identifying a mammal in need of treatment of thedisorder.

In a further aspect, the disorder is a neurological and/or psychiatricdisorder associated with mGluR5 dysfunction. In a further aspect, thedisorder is selected from autism, dementia, delirium, amnesticdisorders, age-related cognitive decline, schizophrenia, including thepositive and negative symptoms thereof and cognitive dysfunction relatedto schizophrena, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, and psychoticdepression. In a yet further aspect, the disorder is selected fromdementia, delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,including absence epilepsy, chorea, pain, migraine, diabetes, dystonia,obesity, eating disorders, brain edema, sleep disorder, narcolepsy,anxiety, affective disorder, panic attacks, unipolar depression, bipolardisorder, psychotic depression, autism, panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, andsubstance-induced anxiety disorder. In an even further aspect, thedisorder is absence epilepsy. In a still further aspect, the disorder isselected from cognitive disorders, age-related cognition decline,learning deficit, intellectual impairment disorders, cognitionimpairment in schizophrenia, cognition impairment in Alzheimer'sdisease, and mild cognitive impairment.

b. Treatment of a Disease of Uncontrolled Cellular Proliferation

In one aspect, the invention relates to a method for the treatment of adisease of uncontrolled cellular proliferation in a mammal comprisingthe step of administering to the mammal at least one disclosed compoundor at least one disclosed product in a dosage and amount effective totreat the disease in the mammal. In a further aspect, the mammal is ahuman. In a further aspect, the mammal has been diagnosed with a needfor treatment of the disease prior to the administering step. In afurther aspect, the method further comprises the step of identifying amammal in need of treatment of the disease.

In a further aspect, the disorder is cancer. In a still further aspect,the cancer is selected from breast cancer, renal cancer, gastric cancer,and colorectal cancer. In a yet further aspect, the disorder is selectedfrom lymphoma, cancers of the brain, genitourinary tract cancer,lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreaticcancer, breast cancer, and malignant melanoma. In an even furtheraspect, the disorder is selected from breast cancer, renal cancer,gastric cancer, colorectal cancer, lymphoma, cancers of the brain,genitourinary tract cancer, lymphatic system cancer, stomach cancer,larynx cancer, lung, pancreatic cancer, and malignant melanoma.

c. Potentiation of Metabotropic Glutamate Receptor Activity

In one aspect, the invention relates to a method for potentiation ofmGluR5 activity in a mammal comprising the step of administering to themammal at least one disclosed compound or at least one disclosed productin a dosage and amount effective to increase mGluR5 activity in themammal either in the presence or absence of the endogenous ligand. In afurther aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for increasing mGluR5 activity prior tothe administering step. In a further aspect, the mammal has beendiagnosed with a need for treatment of a disorder related to mGluR5activity prior to the administering step. In a further aspect, themethod further comprises the step of identifying a mammal in need ofincreasing mGluR5 activity.

In one aspect, the invention relates to a method for potentiation ofmetabotropic glutamate receptor activity in a mammal comprising the stepof administering to the mammal a therapeutically effective amount of atleast one compound having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A1 isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In various aspects, the invention relates to a method for potentiationof metabotropic glutamate receptor activity in a mammal comprising thestep of administering to the mammal at least one disclosed compound orat least one disclosed product in a dosage and amount effective toincrease metabotropic glutamate receptor activity in the mammal eitherin the presence or absence of the endogenous ligand.

In a further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 10,000 nM. In astill further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 5,000 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits positive allosteric modulation ofmGluR5 with an EC₅₀ of less than about 500 nM. In a yet further aspect,the compound exhibits positive allosteric modulation of mGluR5 with anEC₅₀ of less than about 100 nM.

In a further aspect, the compound exhibits potentiation of mGluR5 withan EC₅₀ of less than about 10,000 nM. In a still further aspect, thecompound exhibits potentiation of mGluR5 with an EC₅₀ of less than about5,000 nM. In an even further aspect, the compound exhibits potentiationof mGluR5 with an EC₅₀ of less than about 1,000 nM. In a further aspect,the compound exhibits potentiation of mGluR5 with an EC₅₀ of less thanabout 500 nM. In a yet further aspect, the compound exhibitspotentiation of mGluR5 with an EC₅₀ of less than about 100 nM.

In a further aspect, the compound exhibits potentiation of mGluR5 withan EC₅₀ of between about 10,000 nM to about 1 nM. In a still furtheraspect, the compound exhibits potentiation of mGluR5 with an EC₅₀ ofbetween about 1,000 nM to about 1 nM. In a yet further aspect, thecompound exhibits potentiation of mGluR5 with an EC₅₀ of between about100 nM to about 1 nM. In an even further aspect, the compound exhibitspotentiation of mGluR5 with an EC₅₀ of between about 10 nM to about 1nM. In a still further aspect, potentiation of mGluR5 activity ispositive allosteric modulation of mGluR5 activity.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for potentiation of metabotropicglutamate receptor activity prior to the administering step. In afurther aspect, the method further comprises comprising the step ofidentifying a mammal in need for potentiation of metabotropic glutamatereceptor activity. In a further aspect, the metabotropic glutamatereceptor is mGluR5.

In a yet further aspect, the potentiation of mGluR5 activity treats adisorder associated with mGluR5 activity in the mammal. In a stillfurther aspect, the mammal has been diagnosed with a need for treatmentof the disorder prior to the administering step. In an even furtheraspect, treatment further comprises the step of identifying a mammal inneed of treatment of the disorder.

In a further aspect, potentiation of metabotropic glutamate receptoractivity in a mammal is associated with the treatment of a neurologicaland/or psychiatric disorder associated with mGluR5 dysfunction. In afurther aspect, the disorder is selected from autism, dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, including the positive and negative symptoms thereof andcognitive dysfunction related to schizophrena, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, chorea, pain, migraine,diabetes, dystonia, obesity, eating disorders, brain edema, sleepdisorder, narcolepsy, anxiety, affective disorder, panic attacks,unipolar depression, bipolar disorder, and psychotic depression. In ayet further aspect, the disorder is selected from dementia, delirium,amnestic disorders, age-related cognitive decline, schizophrenia,psychosis including schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,substance-related disorder, movement disorders, epilepsy, includingabsence epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity,eating disorders, brain edema, sleep disorder, narcolepsy, anxiety,affective disorder, panic attacks, unipolar depression, bipolardisorder, psychotic depression, autism, panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, andsubstance-induced anxiety disorder. In an even further aspect, thedisorder is absence epilepsy. In a still further aspect, the disorder isselected from cognitive disorders, age-related cognition decline,learning deficit, intellectual impairment disorders, cognitionimpairment in schizophrenia, cognition impairment in Alzheimer'sdisease, and mild cognitive impairment.

In a further aspect, potentiation of metabotropic glutamate receptoractivity in a mammal is associated with the treatment of a disorderassociated with uncontrolled cellular proliferation. In a furtheraspect, the disorder associated with uncontrolled cellular proliferationis cancer. In a still further aspect, the cancer is selected from breastcancer, renal cancer, gastric cancer, and colorectal cancer. In a yetfurther aspect, the disorder is selected from lymphoma, cancers of thebrain, genitourinary tract cancer, lymphatic system cancer, stomachcancer, larynx cancer, lung, pancreatic cancer, breast cancer, andmalignant melanoma. In an even further aspect, the disorder is selectedfrom breast cancer, renal cancer, gastric cancer, colorectal cancer,lymphoma, cancers of the brain, genitourinary tract cancer, lymphaticsystem cancer, stomach cancer, larynx cancer, lung, pancreatic cancer,and malignant melanoma.

d. Partial Agonism of Metabotropic Glutamate Receptor Activity

In one aspect, the invention relates to a method for partial agonism ofmetabotropic glutamate receptor activity in a mammal. In a furtheraspect, the method relates to a method for partial agonism ofmetabotropic glutamate receptor activity in a mammal by contacting atleast one cell in the mammal, comprising the step of contacting the atleast one cell with at least one disclosed compound or at least onedisclosed product in an amount effective to inhibit mGluR5 activity inthe at least one cell.

In one aspect, the invention relates to a method for partial agonism ofmetabotropic glutamate receptor activity in a mammal comprising the stepof administering to the mammal a therapeutically effective amount of atleast one compound having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A1 isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In a further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 10,000 nM. In astill further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 5,000 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits positive allosteric modulation ofmGluR5 with an EC₅₀ of less than about 500 nM. In a yet further aspect,the compound exhibits positive allosteric modulation of mGluR5 with anEC₅₀ of less than about 100 nM.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for partial agonism of metabotropicglutamate receptor activity prior to the administering step. In a stillfurther aspect, the method further comprises the step of identifying amammal in need for partial agonism of metabotropic glutamate receptoractivity. In a yet further aspect, the metabotropic glutamate receptoris mGluR5.

In a further aspect, partial agonism of metabotropic glutamate receptoractivity in a mammal is associated with the treatment of a neurologicaland/or psychiatric disorder associated with mGluR5 dysfunction. In afurther aspect, the disorder is selected from autism, dementia,delirium, amnestic disorders, age-related cognitive decline,schizophrenia, including the positive and negative symptoms thereof andcognitive dysfunction related to schizophrena, psychosis includingschizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, substance-relateddisorder, movement disorders, epilepsy, chorea, pain, migraine,diabetes, dystonia, obesity, eating disorders, brain edema, sleepdisorder, narcolepsy, anxiety, affective disorder, panic attacks,unipolar depression, bipolar disorder, and psychotic depression. In ayet further aspect, the disorder is selected from dementia, delirium,amnestic disorders, age-related cognitive decline, schizophrenia,psychosis including schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,substance-related disorder, movement disorders, epilepsy, includingabsence epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity,eating disorders, brain edema, sleep disorder, narcolepsy, anxiety,affective disorder, panic attacks, unipolar depression, bipolardisorder, psychotic depression, autism, panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, andsubstance-induced anxiety disorder. In an even further aspect, thedisorder is absence epilepsy. In a still further aspect, the disorder isselected from cognitive disorders, age-related cognition decline,learning deficit, intellectual impairment disorders, cognitionimpairment in schizophrenia, cognition impairment in Alzheimer'sdisease, and mild cognitive impairment.

In a further aspect, partial agonism of metabotropic glutamate receptoractivity in a mammal is associated with the treatment of a disorderassociated with uncontrolled cellular proliferation. In a furtheraspect, the disorder associated with uncontrolled cellular proliferationis cancer. In a still further aspect, the cancer is selected from breastcancer, renal cancer, gastric cancer, and colorectal cancer. In a yetfurther aspect, the disorder is selected from lymphoma, cancers of thebrain, genitourinary tract cancer, lymphatic system cancer, stomachcancer, larynx cancer, lung, pancreatic cancer, breast cancer, andmalignant melanoma. In an even further aspect, the disorder is selectedfrom breast cancer, renal cancer, gastric cancer, colorectal cancer,lymphoma, cancers of the brain, genitourinary tract cancer, lymphaticsystem cancer, stomach cancer, larynx cancer, lung, pancreatic cancer,and malignant melanoma.

e. Enhancing Cognition

In one aspect, the invention relates to a method for enhancing cognitionin a mammal comprising the step of administering to the mammal aneffective amount of at least one disclosed compound.

In one aspect, the invention relates to a method for enhancing cognitionin a mammal comprising the step of administering to the mammal aneffective amount of at least one compound having a structure representedby a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A1 isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In a further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 10,000 nM. In astill further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 5,000 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits positive allosteric modulation ofmGluR5 with an EC₅₀ of less than about 500 nM. In a yet further aspect,the compound exhibits positive allosteric modulation of mGluR5 with anEC₅₀ of less than about 100 nM.

In one aspect, the mammal is a human. In one aspect, the mammal has beendiagnosed with a need for cognition enhancement prior to theadministering step. In a still further aspect, the method furthercomprises the step of identifying a mammal in need of cognitionenhancement prior to the administering step. In a further aspect, thecognition enhancement is a statistically significant increase in NovelObject Recognition. In a further aspect, the cognition enhancement is astatistically significant increase in performance of the Wisconsin CardSorting Test. In a further aspect, the method further comprises the stepof identifying a mammal in need of increasing mGluR5 activity.

f. Modulating mGluR5 Activity in Mammals

In one aspect, the invention relates to a method for modulating mGluR5activity in a mammal comprising the step of administering to the mammalan effective amount of at least one disclosed compound.

In one aspect, the invention relates to a method for modulating mGluR5activity in a mammal comprising the step of administering to the mammalan effective amount of at least one compound having a structurerepresented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A1 isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In a further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 10,000 nM. In astill further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 5,000 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits positive allosteric modulation ofmGluR5 with an EC₅₀ of less than about 500 nM. In a yet further aspect,the compound exhibits positive allosteric modulation of mGluR5 with anEC₅₀ of less than about 100 nM.

In one aspect, modulating is increasing. In a further aspect, modulatingis potentiation. In a further aspect, modulating is partial agonism.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for modulating mGluR5 activity prior tothe administering step. In a further aspect, the mammal has beendiagnosed with a need for treatment of a disorder related to mGluR5activity prior to the administering step. In a further aspect, themethod further comprises the step of identifying a mammal in need ofincreasing mGluR5 activity.

In one aspect, an effective amount is a therapeutically effectiveamount.

In a further aspect, modulating mGluR5 activity in a mammal isassociated with the treatment of a neurological and/or psychiatricdisorder associated with mGluR5 dysfunction. In a further aspect, thedisorder is selected from autism, dementia, delirium, amnesticdisorders, age-related cognitive decline, schizophrenia, including thepositive and negative symptoms thereof and cognitive dysfunction relatedto schizophrena, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, and psychoticdepression. In a yet further aspect, the disorder is selected fromdementia, delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,including absence epilepsy, chorea, pain, migraine, diabetes, dystonia,obesity, eating disorders, brain edema, sleep disorder, narcolepsy,anxiety, affective disorder, panic attacks, unipolar depression, bipolardisorder, psychotic depression, autism, panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, andsubstance-induced anxiety disorder. In an even further aspect, thedisorder is absence epilepsy. In a still further aspect, the disorder isselected from cognitive disorders, age-related cognition decline,learning deficit, intellectual impairment disorders, cognitionimpairment in schizophrenia, cognition impairment in Alzheimer'sdisease, and mild cognitive impairment.

In a further aspect, modulating mGluR5 activity in a mammal isassociated with the treatment of a disorder associated with uncontrolledcellular proliferation. In a further aspect, the disorder associatedwith uncontrolled cellular proliferation is cancer. In a still furtheraspect, the cancer is selected from breast cancer, renal cancer, gastriccancer, and colorectal cancer. In a yet further aspect, the disorder isselected from lymphoma, cancers of the brain, genitourinary tractcancer, lymphatic system cancer, stomach cancer, larynx cancer, lung,pancreatic cancer, breast cancer, and malignant melanoma. In an evenfurther aspect, the disorder is selected from breast cancer, renalcancer, gastric cancer, colorectal cancer, lymphoma, cancers of thebrain, genitourinary tract cancer, lymphatic system cancer, stomachcancer, larynx cancer, lung, pancreatic cancer, and malignant melanoma.

g. Modulating mGluR5 Activity in Cells

In one aspect, the invention relates to a method for modulating mGluR5activity in at least one cell, comprising the step of contacting the atleast one cell with an effective amount of at least one disclosedcompound.

In one aspect, the invention relates to a method for modulating mGluR5activity in at least one cell, comprising the step of contacting the atleast one cell with an effective amount of at least one compound havinga structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when is present and A¹ and A² are joined by acovalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A1 isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound.

In a further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 10,000 nM. In astill further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 5,000 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mGluR5 with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits positive allosteric modulation ofmGluR5 with an EC₅₀ of less than about 500 nM. In a yet further aspect,the compound exhibits positive allosteric modulation of mGluR5 with anEC₅₀ of less than about 100 nM.

In a further aspect, the compound exhibits potentiation of mGluR5 withan EC₅₀ of less than about 10,000 nM. In a still further aspect, thecompound exhibits potentiation of mGluR5 with an EC₅₀ of less than about5,000 nM. In an even further aspect, the compound exhibits potentiationof mGluR5 with an EC₅₀ of less than about 1,000 nM. In a further aspect,the compound exhibits potentiation of mGluR5 with an EC₅₀ of less thanabout 500 nM. In a yet further aspect, the compound exhibitspotentiation of mGluR5 with an EC₅₀ of less than about 100 nM.

In a further aspect, the compound exhibits potentiation of mGluR5 withan EC₅₀ of between about 10,000 nM to about 1 nM. In a still furtheraspect, the compound exhibits potentiation of mGluR5 with an EC₅₀ ofbetween about 1,000 nM to about 1 nM. In a yet further aspect, thecompound exhibits potentiation of mGluR5 with an EC₅₀ of between about100 nM to about 1 nM. In an even further aspect, the compound exhibitspotentiation of mGluR5 with an EC₅₀ of between about 10 nM to about 1nM. In a still further aspect, potentiation of mGluR5 activity ispositive allosteric modulation of mGluR5 activity.

In one aspect, modulating is increasing. In a further aspect, modulatingis potentiation. In a further aspect, modulating is partial agonism.

In one aspect, the cell is mammalian. In a further aspect, the cell ishuman. In a further aspect, the cell has been isolated from a mammalprior to the contacting step.

In a further aspect, contacting is via administration to a mammal. In afurther aspect, the mammal has been diagnosed with a need for modulatingmGluR5 activity prior to the administering step. In a further aspect,the mammal has been diagnosed with a need for treatment of a disorderrelated to mGluR5 activity prior to the administering step.

In one aspect, modulating mGluR5 activity in at least one cell treats aneurological and/or psychiatric disorder. In a further aspect, thedisorder is selected from autism, dementia, delirium, amnesticdisorders, age-related cognitive decline, schizophrenia, including thepositive and negative symptoms thereof and cognitive dysfunction relatedto schizophrena, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders,brain edema, sleep disorder, narcolepsy, anxiety, affective disorder,panic attacks, unipolar depression, bipolar disorder, and psychoticdepression. In a yet further aspect, the disorder is selected fromdementia, delirium, amnestic disorders, age-related cognitive decline,schizophrenia, psychosis including schizophrenia, schizophreniformdisorder, schizoaffective disorder, delusional disorder, brief psychoticdisorder, substance-related disorder, movement disorders, epilepsy,including absence epilepsy, chorea, pain, migraine, diabetes, dystonia,obesity, eating disorders, brain edema, sleep disorder, narcolepsy,anxiety, affective disorder, panic attacks, unipolar depression, bipolardisorder, psychotic depression, autism, panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, andsubstance-induced anxiety disorder. In an even further aspect, thedisorder is absence epilepsy. In a still further aspect, the disorder isselected from cognitive disorders, age-related cognition decline,learning deficit, intellectual impairment disorders, cognitionimpairment in schizophrenia, cognition impairment in Alzheimer'sdisease, and mild cognitive impairment.

In a further aspect, modulating mGluR5 activity in at least one celltreats a disorder associated with uncontrolled cellular proliferation.In a further aspect, the disorder associated with uncontrolled cellularproliferation is cancer. In a still further aspect, the cancer isselected from breast cancer, renal cancer, gastric cancer, andcolorectal cancer. In a yet further aspect, the disorder is selectedfrom lymphoma, cancers of the brain, genitourinary tract cancer,lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreaticcancer, breast cancer, and malignant melanoma. In an even furtheraspect, the disorder is selected from breast cancer, renal cancer,gastric cancer, colorectal cancer, lymphoma, cancers of the brain,genitourinary tract cancer, lymphatic system cancer, stomach cancer,larynx cancer, lung, pancreatic cancer, and malignant melanoma.

2. Cotherapeutic Methods

The present invention is further directed to administration of a mGluR5potentiator for improving treatment outcomes in the context of cognitiveor behavioral therapy. That is, in one aspect, the invention relates toa cotherapeutic method comprising the step of administering to a mammalan effective amount of at least one disclosed compound; at least oneproduct of a disclosed method of making; or a pharmaceutically effectivesalt, hydrate, solvate, or polymorph thereof.

In a further aspect, the mammal is a human. In a still further aspect,an effective amount is a therapeutically effective amount. In a yetfurther aspect, an effective amount is a prophylatically effectiveamount. In an even further aspect, treatment is symptom amelioration orprevention, and wherein an effective amount is a prophylaticallyeffective amount.

In a further aspect, administration improves treatment outcomes in thecontext of cognitive or behavioral therapy. Administration in connectionwith cognitive or behavioral therapy can be continuous or intermittent.Administration need not be simultaneous with therapy and can be before,during, and/or after therapy. For example, cognitive or behavioraltherapy can be provided within 1, 2, 3, 4, 5, 6, or 7 days before orafter administration of the compound. As a further example, cognitive orbehavioral therapy can be provided within 1, 2, 3, or 4 weeks before orafter administration of the compound. As a still further example,cognitive or behavioral therapy can be provided before or afteradministration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 half-lives of the administered compound. It is understood that thedisclosed cotherapeutic methods can be used in connection with thedisclosed compounds, compositions, kits, and uses.

3. Manufacture of a Medicament

In one aspect, the invention relates to a method for the manufacture ofa medicament for potentiation of metabotropic glutamate receptoractivity in a mammal comprising combining a therapeutically effectiveamount of a disclosed compound or product of a disclosed method with apharmaceutically acceptable carrier or diluent.

In various aspect, the invention relates methods for the manufacture ofa medicament for modulating the activity mGluR5 (e.g., treatment of oneor more neurological and/or psychiatric disorder associated with mGluR5dysfunction) in mammals (e.g., humans) comprising combining one or moredisclosed compounds, products, or compositions or a pharmaceuticallyacceptable salt, solvate, hydrate, or polymorph thereof, with apharmaceutically acceptable carrier. It is understood that the disclosedmethods can be performed with the disclosed compounds, products, andpharmaceutical compositions. It is also understood that the disclosedmethods can be employed in connection with the disclosed methods ofusing.

4. Use of Compounds

In one aspect, the invention relates to the use of a disclosed compoundor a product of a disclosed method of making. In a further aspect, theuse relates to the manufacture of a medicament for the treatment of adisorder associated with glutamate dysfunction in a mammal. In a furtheraspect, the disorder is a neurological and/or psychiatric disorder. In afurther aspect, the disorder is a disease of uncontrolled cellularproliferation. In a further aspect, a use relates to treatment of aneurological and/or psychiatric disorder associated with glutamatedysfunction in a mammal.

In a further aspect, a use relates to potentiation of metabotropicglutamate receptor activity in a mammal. In a further aspect, a userelates to partial agonism of metabotropic glutamate receptor activityin a mammal. In a further aspect, a use relates to enhancing cognitionin a mammal. In a further aspect, a use relates to modulating mGluR5activity in a mammal. In a further aspect, a use relates to modulatingmGluR5 activity in a cell.

In one aspect, a use is treatment of a neurological and/or psychiatricdisorder associated with mGluR5 dysfunction. In a further aspect, thedisorder is selected from dementia, delirium, amnestic disorders,age-related cognitive decline, schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,substance-related disorder, movement disorders, epilepsy, chorea, pain,migraine, diabetes, dystonia, obesity, eating disorders, brain edema,sleep disorder, narcolepsy, anxiety, affective disorder, panic attacks,unipolar depression, bipolar disorder, and psychotic depression.

In one aspect, a use is associated with the treatment of a disorderassociated with uncontrolled cellular proliferation. In a furtheraspect, the disorder is cancer. In a still further aspect, the cancer isselected from breast cancer, renal cancer, gastric cancer, andcolorectal cancer. In a further aspect, the disorder is selected fromlymphoma, cancers of the brain, genitourinary tract cancer, lymphaticsystem cancer, stomach cancer, larynx cancer, lung, pancreatic cancer,breast cancer, and malignant melanoma.

In one aspect, the invention relates to the use of a disclosed compoundor a disclosed product in the manufacture of a medicament for thetreatment of a disorder associated with glutamate dysfunction in amammal. In a further aspect, the disorder is a neurological and/orpsychiatric disorder. In a further aspect, the disorder is a disease ofuncontrolled cellular proliferation.

In one aspect, the invention relates to the use of a disclosed compoundor a product of a disclosed method of making, or a pharmaceuticallyacceptable salt, solvate, or polymorph thereof, or a pharmaceuticalcomposition for use in treating or preventing a central nervous systemdisorder selected from the group of psychotic disorders and conditions;anxiety disorders; movement disorders; drug abuse; mood disorders;neurodegenerative disorders; disorders or conditions comprising as asymptom a deficiency in attention and/or cognition; pain and diseases ofuncontrolled cellular proliferation. In a further aspect, the inventionrelates to the use of a disclosed compound or a product of a disclosedmethod of making, or a pharmaceutically acceptable salt, solvate, orpolymorph thereof, or a pharmaceutical composition for use wherein thepsychotic disorders and conditions are selected from the group ofschizophrenia; schizophreniform disorder; schizoaffective disorder;delusional disorder; substance-induced psychotic disorder; personalitydisorders of the paranoid type; and personality disorder of the schizoidtype; the anxiety disorders are selected from the group of panicdisorder; agoraphobia; specific phobia; social phobia;obsessive-compulsive disorder; post-traumatic stress disorder; acutestress disorder; and generalized anxiety disorder; the movementdisorders are selected from the group of Huntington's disease;dyskinesia; Parkinson's disease; restless leg syndrome and essentialtremor; Tourette's syndrome and other tic disorders; thesubstance-related disorders are selected from the group of alcoholabuse; alcohol dependence; alcohol withdrawal; alcohol withdrawaldelirium; alcohol-induced psychotic disorder; amphetamine dependence;amphetamine withdrawal; cocaine dependence; cocaine withdrawal; nicotinedependence; nicotine withdrawal; opioid dependence and opioidwithdrawal; the mood disorders are selected from depression, mania andbipolar disorder of types I and II; cyclothymic disorder; depression;dysthymic disorder; major depressive disorder and substance-induced mooddisorder; the neurodegenerative disorders are selected from the group ofParkinson's disease; Huntington's disease; dementia such as for exampleAlzheimer's disease; multi-infarct dementia; AIDS-related dementia orfrontotemporal dementia; the disorders or conditions comprising as asymptom a deficiency in attention and/or cognition are selected from thegroup of dementia, such as Alzheimer's disease; multi-infarct dementia;dementia due to Lewy body disease; alcoholic dementia orsubstance-induced persisting dementia; dementia associated withintracranial tumors or cerebral trauma; dementia associated withHuntington's disease; dementia associated with Parkinson's disease;AIDS-related dementia; dementia due to Pick's disease; dementia due toCreutzfeldt-Jakob disease; delirium; amnestic disorder; post-traumaticstress disorder; stroke; progressive supranuclear palsy; mentalretardation; a learning disorder; attention-deficit/hyperactivitydisorder (ADHD); mild cognitive disorder; Asperger's syndrome; andage-related cognitive impairment; pain includes acute and chronicstates, severe pain, intractable pain, neuropathic pain andpost-traumatic pain, cancer pain, non-cancer pain, pain disorderassociated with psychological factors, pain disorder associated with ageneral medical condition or pain disorder associated with bothpsychological factors and a general medical condition; the diseases ofuncontrolled cellular proliferation are selected from lymphoma, cancersof the brain, genitourinary tract cancer, lymphatic cancer, stomachcancer, larynx cancer, lung cancer, pancreatic cancer, breast cancer,and malignant melanoma.

In one aspect, the invention relates to the use of a disclosed compoundor a product of a disclosed method of making, or a pharmaceuticallyacceptable salt, solvate, or polymorph thereof, or a pharmaceuticalcomposition, in combination with an additional pharmaceutical agent foruse in the treatment or prevention of a central nervous system disorderselected from the group of psychotic disorders and conditions; anxietydisorders; movement disorders; drug abuse; mood disorders;neurodegenerative disorders; disorders or conditions comprising as asymptom a deficiency in attention and/or cognition; pain and diseases ofuncontrolled cellular proliferation.

In one aspect, the invention relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method of making, ora pharmaceutically acceptable salt, solvate, or polymorph thereof,characterized in that a pharmaceutically acceptable carrier isintimately mixed with a therapeutically effective amount of the compoundor the product of a disclosed method of making.

In a further aspect, the invention relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method of making, ora pharmaceutically acceptable salt, solvate, or polymorph thereof, foruse as a medicament.

5. Kits

In one aspect, the invention relates to a kit comprising a disclosedcompound or a product of a disclosed method and one or more of at leastone agent known to increase mGluR5 activity; at least one agent known todecrease mGluR5 activity; at least one agent known to treat aneurological and/or psychiatric disorder; at least one agent known totreat a disease of uncontrolled cellular proliferation; or instructionsfor treating a disorder associated with glutamate dysfunction. In afurther aspect, the at least one compound or the at least one productand the at least one agent are co-formulated. In a further aspect, theat least one compound or the at least one product and the at least oneagent are co-packaged.

In various aspects, the invention relates to products and kitscontaining as a first active ingredient a compound according to theinvention, as defined herein, and as a second active ingredient one ormore components, as combined preparations for simultaneous, separate, orsequential use in the treatment of a neurological and/or psychiatricdisorder. In a further aspect, the invention relates to products andkits containing as a first active ingredient a compound according to theinvention, as defined herein, and as a second active ingredient one ormore components, as combined preparations for simultaneous, separate, orsequential use in the treatment of a disease of uncontrolled cellularproliferation. In a still further aspect, the invention relates toproducts and kits containing as a first active ingredient a compoundaccording to the invention, as defined herein, and as a second activeingredient one or more components, as combined preparations forsimultaneous, separate, or sequential use in the treatment of a diseaserelated to a need to increase mGluR5 activity. In an even furtheraspect, the invention relates to products and kits containing as a firstactive ingredient a compound according to the invention, as definedherein, and as a second active ingredient one or more components, ascombined preparations for simultaneous, separate, or sequential use inthe treatment of a disease related to a metabotropic glutamate receptordysfunction.

In one aspect, the invention relates to a kit comprising at least onecompound having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2c), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof; and one or more of: (a) at leastone agent known to increase mGluR5 activity; (b) at least one agentknown to decrease mGluR5 activity; (c) at least one agent known to treata neurological and/or psychiatric disorder; (d) at least one agent knownto treat a disease of uncontrolled cellular proliferation; or (e)instructions for treating a disorder associated with glutamatedysfunction.

In a further aspect, the kit comprises a disclosed compound or a productof a disclosed method.

In a further aspect, the at least one compound and the at least oneagent are co-formulated. In a still further aspect, the at least onecompound and the at least one agent are co-packaged.

The kits can also comprise compounds and/or products co-packaged,co-formulated, and/or co-delivered with other components. For example, adrug manufacturer, a drug reseller, a physician, a compounding shop, ora pharmacist can provide a kit comprising a disclosed compound and/orproduct and another component for delivery to a patient.

It is contemplated that the disclosed kits can be used in connectionwith the disclosed methods of making, the disclosed methods of using,and/or the disclosed compositions.

6. Non-Medical Uses

Also provided are the uses of the disclosed compounds and products aspharmacological tools in the development and standardization of in vitroand in vivo test systems for the evaluation of the effects ofpotentiators of mGluR5 related activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents of mGluR5. In a further aspect, the inventionrelates to the use of a disclosed compound or a disclosed product aspharmacological tools in the development and standardization of in vitroand in vivo test systems for the evaluation of the effects ofpotentiators of mGluR5 related activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents of mGluR5.

G. EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.

The following exemplary compounds of the invention were synthesized. TheExamples are provided herein to illustrate the invention, and should notbe construed as limiting the invention in any way. The Examples aretypically depicted in free base form, according to the IUPAC namingconvention. However, some of the Examples were obtained or isolated insalt form.

As indicated, some of the Examples were obtained as racemic mixtures ofone or more enantiomers or diastereomers. The compounds may be separatedby one skilled in the art to isolate individual enantiomers. Separationcan be carried out by the coupling of a racemic mixture of compounds toan enantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. A racemicor diastereomeric mixture of the compounds can also be separateddirectly by chromatographic methods using chiral stationary phases.

1. General Methods

¹H NMR spectra were recorded either on a Bruker DPX-400 or on a BrukerAV-500 spectrometer with standard pulse sequences, operating at 400 MHzand 500 MHz respectively. Chemical shifts (δ) are reported in parts permillion (ppm) downfield from tetramethylsilane (TMS), which was used asinternal standard. Coupling constants (J-values) are expressed in Hzunits.

Microwave assisted reactions were performed in a single-mode reactor:Emrys™ Optimizer microwave reactor (Personal Chemistry A.B., currentlyBiotage).

Hydrogenation reactions were performed in a continuous flowhydrogenator: H-CUBE® from ThalesNano Nanotechnology Inc.

Thin layer chromatography (TLC) was carried out on silica gel 60 F254plates (Merck) using reagent grade solvents. Open column chromatographywas performed on silica gel, particle size 60 Å, mesh=230-400 (Merck)under standard techniques. Flash column chromatography was performedusing ready-to-connect cartridges from: (a) ISCO, on irregular silicagel, particle size 15-40 μm (normal layer disposable flash columns) on aCompanion system from ISCO, Inc.; or, (b) Merck, on irregular silicagel, particle size 15-40 μm (normal layer disposable flash columns) onan SPOT or LAFLASH system from Armen Instrument.

Melting point values are peak values, and are obtained with experimentaluncertainties that are commonly associated with this analytical method.For a number of compounds, melting points were determined in opencapillary tubes either on a Mettler FP62 or on a Mettler FP81HT-FP90apparatus. Melting points were measured with a temperature gradient of10° C./minute. Maximum temperature was 300° C. The melting point wasread from a digital display.

Analytical HPLC was performed on an HP1100 with UV detection at 214 and254 nm along with ELSD detection and low resolution mass spectra usingan Agilent 1200 series 6130 mass spectrometer.

Preparative RP-HPLC purification was performed on a custom HP1100automated purification system with collection triggered by massdetection or using a Gilson Inc. preparative UV-based system using aPhenomenex Luna C18 column (50×30 mm I.D., 5 μm) with an acetonitrile(unmodified)-water (0.1% TFA) custom gradient.

2. LC-MS Methods

a. General Procedure A

The UPLC (Ultra Performance Liquid Chromatography) measurement wasperformed using an Acquity UPLC (Waters) system comprising a samplerorganizer, a binary pump with degasser, a four column's oven, adiode-array detector (DAD) and a column as specified in the respectivemethods below. Column flow was used without split to the MS detector.The MS detector was configured with an ESCI dual ionization source(electrospray combined with atmospheric pressure chemical ionization).Nitrogen was used as the nebulizer gas. The source temperature wasmaintained at 140° C. Data acquisition was performed withMassLynx-Openlynx software. [M+H], means the protonated mass of the freebase of the compound and where indicated R_(t) means retention time (inminutes).

b. General Procedure B

The HPLC measurement was performed using an HP 1100 (AgilentTechnologies) system comprising a pump (quaternary or binary) withdegasser, an autosampler, a column oven, a diode-array detector (DAD)and a column as specified in the respective methods below. Flow from thecolumn was split to the MS spectrometer. The MS detector was configuredwith an electrospray ionization source. Nitrogen was used as thenebulizer gas. The source temperature was maintained at 140° C. Dataacquisition was performed with MassLynx-Openlynx software.

c. LCMS Method 1

In addition to the general procedure A: Reversed phase UPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 1.0 mL/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B in 3.8minutes, to 5% A, 95% B in 4.6 minutes, kept till 5.0 minutes. Injectionvolume was 2.0 μl. Low-resolution mass spectra (single quadrupole, SQDdetector) were acquired by scanning from 100 to 1000 in 0.1 secondsusing an inter-channel delay of 0.08 seconds. The capillary needlevoltage was 3 kV. The cone voltage was 25 V for positive ionization modeand 30 V for negative ionization mode.

d. LCMS Method 2

Same gradient as LCMS Method 1; column used: RRHD Eclipse Plus-C18 (1.8μm 2.1×50 mm) from Agilent.

e. LCMS Method 3

In addition to the general procedure A: Reversed phase UPLC was carriedout on a RRHD Eclipse Plus-C18 (1.8 μm 2.1×50 mm) from Agilent, with aflow rate of 1.0 ml/min, at 50° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (acetonitrile), to 5% A, 95% B in 4.6minutes, kept till 5.0 minutes. Injection volume 2.0 μl. Low-resolutionmass spectra (single quadrupole, SQD detector) were acquired by scanningfrom 100 to 1000 in 0.1 seconds using an inter-channel delay of 0.08seconds. The capillary needle voltage was 3 kV. The cone voltage was 25V for positive ionization mode and 30 V for negative ionization mode.

f. LCMS Method 4

In addition to the general procedure B: Reversed phase HPLC was carriedout on a Eclipse Plus-C18 column (3.5 μm 2.1×30 mm) from Agilent, with aflow rate of 1.0 ml/min, at 60° C. The gradient conditions used are: 95%A (0.5 g/l ammonium acetate solution+5% acetonitrile), 5% B (mixture ofacetonitrile/methanol, 1/1) to 100% B in 5.0 minutes, kept till 5.15minutes and equilibrated to initial conditions at 5.3 minutes until 7.0minutes. Injection volume 2 High-resolution mass spectra (Time ofFlight, TOF detector) were acquired by scanning from 100 to 750 in 0.5seconds using a dwell time of 0.3 seconds. The capillary needle voltagewas 2.5 kV for positive ionization mode and 2.9 kV for negativeionization mode. The cone voltage was 20 V for both positive andnegative ionization modes. Leucine-Enkephaline was the standardsubstance used for the lock mass calibration.

g. LCMS Method 5

In addition to the general procedure B: Reversed phase HPLC was carriedout on an Eclipse Plus-C18 column (3.5 μm 2.1×30 mm) from Agilent, witha flow rate of 1.0 ml/min, at 60° C. without split to the MS detector.The gradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% acetonitrile), 5% B (mixture of acetonitrile/methanol, 1/1),to 100% B in 5.0 minutes, kept till 5.15 minutes and equilibrated toinitial conditions at 5.30 minutes until 7.0 minutes. Injection volume 2μl. Low-resolution mass spectra (single quadrupole, SQD detector) wereacquired by scanning from 100 to 1000 in 0.1 second using aninter-channel delay of 0.08 seconds. The capillary needle voltage was 3kV. The cone voltage was 20 V for positive ionization mode and 30 V fornegative ionization mode.

3. Preparation of7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine

1,3-Dichloroacetone (2.89 g, 22.77 mmol) was added to a solution6-chloro-2-methylsulfanyl-pyrimidin-4-ylamine (4 g, 22.77 mmol) in AcOH(15 mL) and the mixture was stirred at 110° C. for 16 hours. Then H₂Owas added and the solid formed was filtered off and dried in vacuo toyield 7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine(2.5 g, 44% yield) as a pale brown solid that was used in the next stepwithout further purification.

4. Preparation of7-chloro-5-methylsulfanyl-2-phenoxymethyl-imidazo[1,2-c]pyrimidine

Phenol (0.050 g, 0.53 mmol) was added to a suspension of7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine (0.15g, 0.53 mmol) and K₂CO₃ (0.21 g, 1.58 mmol) in ACN (2 mL). The mixturewas stirred at 50° C. for 18 hours and then the solvents were evaporatedin vacuo. The crude product was purified by flash column chromatography(silica; DCM). The desired fractions were collected and the solventsevaporated in vacuo. The product was triturated with diethyl ether andthe solid thus obtained, filtered and dried in vacuo to yield7-chloro-5-methylsulfanyl-2-phenoxymethyl-imidazo[1,2-c]pyrimidine(0.085 g, 53% yield) as a white solid.

5. Preparation of7-chloro-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one

A solution of lithium hydroxide (66 mg, 2.75 mmol) in H₂O (10 mL) wasadded to a solution of7-chloro-5-methylsulfanyl-2-phenoxymethyl-imidazo[1,2-c]pyrimidine (0.70g, 2.29 mmol) in THF (10 mL). The mixture was stirred at 50° C. for 4hours and then diluted with DCM. The organic layer was separated, dried(Na₂SO₄), filtered and the solvents evaporated in vacuo to yield7-chloro-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.62 g, 98%yield) as a white solid that was used in the next step without furtherpurification.

6. Preparation of 2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one

10% Palladium hydroxide (0.43 g, 3 mmol) was added to a solution of7-chloro-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.24 g, 0.85mmol) and TEA (0.6 mL, 4.32 mmol) in a mixture of AcOEt and MeOH (60mL). The mixture was hydrogenated in a Parr reactor (45 psi) at 50° C.for 16 hours. Then 10% palladium hydroxide (0.18 g, 0.43 mmol) was addedand the mixture hydrogenated again in a Parr reactor (45 psi) at 50° C.for 16 hours. The mixture was hydrogenated over 5 cycles with additionof 10% palladium hydroxide (0.18 g, 0.43 mmol) every cycle. The mixturewas filtered through a pad of diatomaceous earth and washed with MeOH.The solvents were evaporated in vacuo and the crude product purified byflash column chromatography (silica; 7 M solution of ammonia in MeOH inDCM with a gradient of 0/100 to 40/60). The desired fractions werecollected and the solvents evaporated in vacuo to yield2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.19 g, 92% yield) asa white solid.

7. Preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one

TMEDA (8 mL, 54 mmol) was added to a stirred suspension of cytosine (3g, 27 mmol), 4-fluorophenylboronic acid (7.55 g, 5 mmol) andcopper(II)acetate monohydrate (5.44 g, 27 mmol) in a mixture of MeOH(960 mL) and H₂O (240 mL). The mixture was stirred at RT for 16 hours.The solvents were evaporated in vacuo and the crude product purified byopen column chromatography (silica; MeOH in DCM with a gradient of 0/100to 100/0). The desired fractions were collected and the solventsevaporated in vacuo. The product was triturated with MeOH and DCM andthe solid formed filtered and dried in vacuo to yield4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (3.3 g, 60% yield) as awhite solid.

8. Preparation of 4-amino-1-(4-fluoro-phenyl)-5-iodo-1H-pyrimidin-2-one

Sodium metaperiodate (0.21 g, 0.97 mmol) and iodine (0.495 g, 1.95 mmol)were added to a stirred solution of4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (1 g, 4.87 mmol) in amixture of acetic acid (12 mL), water (3 mL) and H₂SO₄ (0.4 mL). Themixture was stirred at 80° C. for 4 hours. The mixture was poured ontoan ice-cold 10% aqueous solution of Na₂SO₃ and then neutralized with a2N aqueous solution of NaOH to pH 7. A solid was formed, filtered andwashed with water and EtOH to yield4-amino-1-(4-fluoro-phenyl)-5-iodo-1H-pyrimidin-2-one (1.35 g, 84%yield) as a white solid, that was used in the next step without furtherpurification.

9. Preparation of2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one

1,3-Dichloroacetone (2.27 g, 11.92 mmol) was added to a solution of4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (4.6 g, 12 mmol) in DMF(135 mL). The mixture was stirred at 150° C. for 30 minutes undermicrowave irradiation and then the solvent was evaporated in vacuo. Thecrude product was purified by flash column chromatography (silica; AcOEtin DCM with a gradient of 0/100 to 30/70). The desired fractions werecollected and the solvents evaporated in vacuo to yield2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (2.5g, 75% yield) as a solid.

10. Preparation of2-chloromethyl-6-(3-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one

2-chloromethyl-6-(3-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one wasprepared from cytosine and 3-fluorophenylboronic acid using the methodsas described above for the preparation of4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

11. Preparation of2-chloromethyl-6-(3,4-difluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one

2-chloromethyl-6-(3,4-difluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-onewas prepared from cytosine and 3,4-difluorophenylboronic acid using themethods as described above for the preparation of4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

12. Preparation of2-chloromethyl-6-(3-Trifluoromethyl-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one

2-chloromethyl-6-(3-trifluoromethyl-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-onewas prepared from cytosine and 3-(trifluoromethyl)phenylboronic acidusing the methods as described above for the preparation of4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

13. Preparation of2-chloromethyl-6-(4-fluoro-phenyl)-7-methyl-6H-imidazo[1,2-c]pyrimidin-5-one

2-Chloromethyl-6-(4-fluoro-phenyl)-7-methyl-6H-imidazo[1,2-c]pyrimidin-5-onewas prepared from 4-amino-6-methyl-1H-pyrimidin-2-one and4-fluorophenylboronic acid using the methods as described above for thepreparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

14. Preparation of 4-amino-1-benzyl-1H-pyrimidin-2-one

A 0.1 M solution of tetra-N-butylammonium hydroxide in a mixture of MeOHand 2-propanol (90 mL, 9.0 mmol) was added dropwise to a stirredsuspension of cytosine (1 g, 9.0 mmol) in DMF (70 mL). The solutionbecame clear and benzyl bromide (2.14 mL, 18 mmol) was added dropwise.The reaction mixture was stirred at RT for 2 hours and then the solventswere evaporated in vacuo. The crude product was purified by flash columnchromatography (silica; MeOH in DCM with a gradient of 0/100 to 50/50).The desired fractions were collected and the solvents evaporated invacuo to yield 4-amino-1-benzyl-1H-pyrimidin-2-one (1 g, 57% yield) as awhite solid.

15. Preparation of 4-amino-1-methyl-1H-pyrimidin-2-one

4-Amino-1-methyl-1H-pyrimidin-2-one was prepared from cytosine andmethyliodide using the methods described above for the preparation of4-amino-1-benzyl-1H-pyrimidin-2-one.

16. Preparation of 4-amino-1-cyclopropylmethyl-1H-pyrimidin-2-one

4-Amino-1-cyclopropylmethyl-1H-pyrimidin-2-one was prepared fromcytosine and (bromomethyl)cyclopropane using the methods described abovefor the preparation of 4-amino-1-benzyl-1H-pyrimidin-2-one.

17. Preparation of6-benzyl-2-chloromethyl-6H-imidazo[1,2-c]pyrimidin-5-one

6-Benzyl-2-chloromethyl-6H-imidazo[1,2-c]pyrimidin-5-one was preparedfrom 4-amino-1-benzyl-1H-pyrimidin-2-one and 1,3-dichloroacetone usingthe methods described above for the preparation of2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

18. Preparation of2-chloromethyl-6-methyl-6H-imidazo[1,2-c]pyrimidin-5-one

2-Chloromethyl-6-methyl-6H-imidazo[1,2-c]pyrimidin-5-one was preparedfrom 4-amino-1-methyl-1H-pyrimidin-2-one and 1,3-dichloroacetone usingthe methods described above for the preparation of2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

19. Preparation of2-chloromethyl-6-cyclopropylmethyl-6H-imidazo[1,2-c]pyrimidin-5-one

2-Chloromethyl-6-cyclopropylmethyl-6H-imidazo[1,2-c]pyrimidin-5-one wasprepared from 4-amino-1-cyclopropylmethyl-1H-pyrimidin-2-one and1,3-dichloroacetone using the methods described above for thepreparation of2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

20. Preparation of2-Chloromethyl-8-fluoro-6-(4-fluoro-phenyl)-6H-imidazo[1,2-C]pyrimidin-5-one

2-Chloromethyl-8-fluoro-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-onewas prepared from 5-fluorocytosine and 4-fluorophenylboronic acid usingthe methods as described above for the preparation of4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

21. Preparation of2-Chloromethyl-6-(4-fluoro-phenyl)-8-iodo-6H-imidazo[1,2-c]pyrimidin-5-one

2-Chloromethyl-6-(4-fluoro-phenyl)-8-iodo-6H-imidazo[1,2-c]pyrimidin-5-onewas prepared from 4-amino-1-(4-fluoro-phenyl)-5-iodo-1H-pyrimidin-2-oneand 1,3-dichloroacetone using the methods as described above for thepreparation of2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.

22. Preparation of3-Bromo-2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one

N-bromosuccinimide (80.4 mg, 0.45 mmol) was added to a stirred solutionof 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one(0.114 g, 0.41 mmol) and benzoyl peroxide (9.94 mg, 0.041 mmol) in DCE(3 mL). The mixture was stirred at RT for 16 hours. The solvent wasevaporated in vacuo and the crude product was purified by flash columnchromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80).The desired fractions were collected and the solvents evaporated invacuo to yield3-bromo-2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one(0.102 g, 70% yield) as a white solid.

23. Preparation of6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one

Phenol (40 mg, 0.24 mmol) was added to a stirred suspension of2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one(0.107 g, 0.38 mmol) and K₂CO₃ (0.160 g, 1.15 mmol) in ACN (3 mL). Themixture was stirred at 90° C. for 16 hours and then the solvents wereevaporated in vacuo. The crude product was purified by flash columnchromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80).The desired fractions were collected and the solvents evaporated invacuo. The product was triturated with diethyl ether to yield6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(0.12 g, 90% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.20(s, 2H), 6.70 (d, J=7.8 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 7.03 (d, J=8.1Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.19-7.25 (m, 2H), 7.27-7.34 (m, 2H),7.38-7.45 (m, 2H), 7.83 (s, 1H).

24. Preparation of6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one

Copper(I)iodide (11.8 mg, 0.062 mmol) was added to a stirred suspensionof 2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (50 mg, 0.21 mmol),4-fluoroiodobenzene (72.5 mg, 0.41 mmol), K₂CO₃ (57 mg, 0.41 mmol) andN,N′-dimethylethylenediamine (0.011 mL, 0.1 mmol) in toluene (1 mL) in asealed tube. The mixture was stirred at 120° C. for 16 hours. Themixture was filtered through a pad of diatomaceous earth and then thesolvent was evaporated in vacuo. The crude product was purified by flashcolumn chromatography (silica; AcOEt in DCM with a gradient of 0/100 to30/70). The desired fractions were collected and evaporated in vacuo toyield6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (45mg, 65% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) 8 ppm 5.20 (s,2H), 6.70 (d, J=7.8 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 7.03 (d, J=8.1 Hz,2H), 7.12 (d, J=7.8 Hz, 1H), 7.19-7.25 (m, 2H), 7.27-7.34 (m, 2H),7.38-7.45 (m, 2H), 7.83 (s, 1H).

25. Preparation of6-(2-Methoxy-pyrimidin-4-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one

Palladium(II)acetate (4.2 mg, 0.019 mmol) was added to a stirredsuspension of 2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (150 mg,0.62 mmol), 4-chloro-2-methoxy-pyrimidine (107.9 mg, 0.75 mmol), Cs₂CO₃(283.6 mg, 0.87 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triiso-propyl-1,1′-biphenyl (26.7 mg,0.056 mmol) in 1,4-dioxane (2 mL) under nitrogen and in a sealed tube.The mixture was stirred at 100° C. for 3 days and at 140° C. for 15minutes under microwave irradiation. The solvent was evaporated in vacuoand the crude product was purified by flash column chromatography(silica; AcOEt in DCM with a gradient of 0/100 to 100/0). The desiredfractions were collected and the solvents evaporated in vacuo. Theproduct was triturated with diethyl ether to yield6-(2-methoxy-pyrimidin-4-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(43 mg, 20% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.09(s, 3H), 5.18 (d, J=0.9 Hz, 2H), 6.77 (dd, J=8.2, 0.6 Hz, 1H), 6.95-7.06(m, 3H), 7.27-7.36 (m, 2H), 7.85 (d, J=0.7 Hz, 1H), 7.91 (d, J=5.5 Hz,1H), 8.24 (d, J=8.1 Hz, 1H), 8.65 (d, J=5.5 Hz, 1H).

26. Preparation of6-(4-Fluoro-phenyl)-8-methyl-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one

Tetrakis(triphenylphosphine)palladium(0) (2.63 mg, 0.0023 mmol) wasadded to a stirred suspension of6-(4-fluoro-phenyl)-8-iodo-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(35 mg, 0.076 mmol), methylboronic acid (22.7 mg, 0.38 mmol) and K₂CO₃(31.5 mg, 0.23 mmol) in a mixture of 1,4-dioxane (4 mL) and DMF (1 mL)under nitrogen and in a sealed tube. The mixture was stirred at 150° C.for 45 minutes under microwave irradiation. The solvents were evaporatedin vacuo and the crude product was purified by flash columnchromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80).The desired fractions were collected and the solvents evaporated invacuo to yield6-(4-fluoro-phenyl)-8-methyl-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(19 mg, 72% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 2.36(d, J=1.2 Hz, 3H), 5.22 (s, 2H), 6.92 (d, J=1.2 Hz, 1H), 6.97 (br. t,J=7.4, 7.4 Hz, 1H), 7.02 (br. d, J=8.1 Hz, 2H), 7.16-7.24 (m, 2H),7.27-7.34 (m, 2H), 7.36-7.44 (m, 2H), 7.84 (s, 1H).

27. Preparation of3-Chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one

N-chlorosuccinimide (32.9 mg, 0.25 mmol) was added to a stirred solutionof 6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(75 mg, 0.22 mmol) in DMF (3.5 mL). The mixture was stirred at 150° C.for 15 minutes under microwave irradiation. The solvent was evaporatedin vacuo and the crude product was purified by flash columnchromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80).The desired fractions were collected and the solvents evaporated invacuo. The product was triturated with DIPE to yield3-chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(46 mg, 56% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) 8 ppm 5.12(s, 2H), 6.62 (d, J=7.9 Hz, 1H), 6.98 (tt, J=7.4, 0.9 Hz, 1H), 7.03-7.07(m, 2H), 7.06 (d, J=7.6 Hz, 1H), 7.17-7.25 (m, 2H), 7.27-7.34 (m, 2H),7.35-7.43 (m, 2H).

28. Preparation of6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

10% Palladium hydroxide (10 mg, 0.07 mmol) was added to a stirredsolution of6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (47mg, 0.14 mmol) in MeOH (50 mL). The mixture was hydrogenated in a Parrreactor at room temperature under H₂ atmosphere for 6 hours. Then themixture was hydrogenated other 7 cycles in a Parr reactor (50 psi) at50° C. for 16 hours with addition of 10% palladium hydroxide (10 mg,0.07 mmol) every cycle. The mixture was filtered through a pad ofdiatomaceous earth and the solvents were evaporated in vacuo. The crudeproduct was purified by flash column chromatography (silica; AcOEt inDCM with a gradient of 0/100 to 50/50). The desired fractions werecollected and the solvents evaporated in vacuo to yield6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(27 mg, 57% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) 8 ppm 3.29(t, J=6.7 Hz, 2H), 4.00 (t, J=6.7 Hz, 2H), 5.02 (d, J=0.7 Hz, 2H),6.94-6.99 (m, 1H), 6.99-7.05 (m, 2H), 7.10-7.17 (m, 2H), 7.27-7.35 (m,4H), 7.57 (s, 1H).

29. Preparation of2-(3-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

Drops of water were added to a stirred suspension of 2 M aqueoussolution of HCl (0.78 mL, 1.57 mmol) and6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(554 mg, 1.57 mmol) in MeOH (110 mL) until a clear solution wasobtained. The mixture was hydrogenated in a H-cube reactor (1 mL/min, 30mm 20% palladium hydroxide on carbon cartridge, 60° C., full hydrogenmode) then (2 mL/min, 30 mm 20% palladium hydroxide on carbon cartridge,80° C., full hydrogen mode) then (3 mL/min, 30 mm 20% palladiumhydroxide on carbon cartridge, 80° C., full hydrogen mode) and then (3mL/min, 30 mm 20% palladium hydroxide on carbon cartridge, 80° C., fullhydrogen mode). The solvents were evaporated in vacuo. The residue wasmade basic with a saturated solution of NaHCO₃ and extracted with DCM.The organic layer was separated, dried (Na₂SO₄), filtered and thesolvents evaporated in vacuo. The crude product was purified by flashcolumn chromatography (silica; AcOEt in DCM with a gradient of 0/100 to50/50). The desired fractions were collected and the solvents evaporatedin vacuo to yield a white solid and an impure fraction which waspurified by flash column chromatography (silica; AcOEt in DCM with agradient of 0/100 to 20/80) to yield as a white solid. The two solidswere combined to yield2-(3-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(327 mg, 58% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 3.29(t, J=6.6 Hz, 2H), 4.01 (t, J=6.8 Hz, 2H), 5.00 (s, 2H), 6.68 (td,J=8.3, 2.2 Hz, 1H), 6.73 (dt, J=11.0, 2.3 Hz, 1H), 6.79 (dd, J=8.2, 2.2Hz, 1H), 7.10-7.18 (m, 2H), 7.20-7.26 (m, 1H), 7.29-7.35 (m, 2H), 7.57(s, 1H).

30. Preparation of2-(4-Fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

A solution of2-(4-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one(0.1 g, 0.28 mmol) in EtOH (25 mL) was hydrogenated in a H-cube reactor(1 mL/min, 30 mm Raney nickel cartridge, 35° C., full hydrogen mode, 3cycles) and then (1 mL/min, 30 mm Raney nickel cartridge, 40° C., fullhydrogen mode, 3 cycles). The solvent was evaporated in vacuo and thecrude product was purified by flash column chromatography (silica; AcOEtin DCM with a gradient of 50/50 to 75/25). The desired fractions werecollected and the solvents evaporated in vacuo to yield2-(4-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(45 mg, 45% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 3.29 (t, J=6.6 Hz,2H), 4.00 (t, J=6.6 Hz, 2H), 4.98 (s, 2H), 6.92-7.01 (m, 4H), 7.10-7.18(m, 2H), 7.29-7.36 (m, 2H), 7.56 (s, 1H).

31. Preparation of6-(5-Methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

A 1.25 M solution of HCl in MeOH (3 mL) was added to a stirred solutionof6-(5-methyl-pyridin-2-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(0.1 g, 0.3 mmol) in MeOH (10 mL) was hydrogenated in a H-cube reactor(1 mL/min, 30 mm Raney nickel cartridge, 30° C., full hydrogen mode, 4cycles) and then (1 mL/min, 30 mm Raney nickel cartridge, RT, fullhydrogen mode, 1 cycle). The solvents were evaporated in vacuo and thecrude product was purified by flash column chromatography (silica; AcOEtin DCM with a gradient of 0/100 to 100/0 and then 7 M solution ofammonia in MeOH in DCM with a gradient of 0/100 to 2/98). The desiredfractions were collected and the solvents evaporated in vacuo. Theproduct was repurified by RP HPLC (C18 XBridge 19×100 5 um, gradientfrom 80% of 0.1% solution of ammonium formate/ammonium hydroxide bufferpH 9 solution in water and 20% CH₃CN to 0% of 0.1% solution of ammoniumformate/ammonium hydroxide buffer pH 9 solution in water and 100% ACN)to yield6-(5-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(5 mg, 5% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 2.35 (s, 3H), 3.24 (t,J=6.6 Hz, 2H), 4.35 (t, J=6.6 Hz, 2H), 5.03 (s, 2H), 6.97 (br. t, J=7.4,7.4 Hz, 1H), 6.99-7.05 (m, 2H), 7.27-7.33 (m, 2H), 7.57 (dd, J=8.5, 2.2Hz, 1H), 7.59 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 8.25 (dd, J=1.6, 0.7 Hz,1H).

32. Preparation of6-(4-Fluoro-phenyl)-2-m-Tolyloxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

Activated Raney nickel (a portion of spatula) was added to a suspensionof6-(4-fluoro-phenyl)-2-m-tolyloxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(70 mg, 0.2 mmol) in MeOH (20 mL). The mixture was hydrogenated at RTunder H₂ atmosphere for 3 days. The mixture was filtered through a padof diatomaceous earth and the solvents were evaporated in vacuo. Thecrude product was purified by flash column chromatography (silica; AcOEtin DCM with a gradient of 50/50 to 75/25). The desired fractions werecollected and the solvents evaporated in vacuo to yield6-(4-fluoro-phenyl)-2-m-tolyloxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(34 mg, 48% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 2.33 (s, 3H), 3.29 (t,J=6.6 Hz, 2H), 4.00 (t, J=6.6 Hz, 2H), 5.01 (s, 2H), 6.76-6.88 (m, 3H),7.09-7.21 (m, 3H), 7.28-7.36 (m, 2H), 7.56 (s, 1H).

33. Preparation of6-(5-Fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

A solution of6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one(20 mg, 0.057 mmol) in a mixture of DMF (0.6 mL) and MeOH (0.6 mL) washydrogenated in a H-cube reactor (1 mL/min, 30 mm Raney nickelcartridge, 80° C., full hydrogen mode, 1 cycle). The solvents wereevaporated in vacuo and the crude product was purified by RP HPLC (C18XBridge 19×100 5 um, gradient from 80% of 0.1% solution of ammoniumformate/ammonium hydroxide buffer pH 9 solution in water and 20% CH₃CNto 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH9 solution in water and 100% ACN) to yield6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(8.2 mg, 41% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.49 (d, J=3.0 Hz,3H), 3.24 (t, J=6.7 Hz, 2H), 4.35 (t, J=6.7 Hz, 2H), 5.02 (s, 2H), 6.97(br. t, J=7.4, 7.4 Hz, 1H), 7.00-7.05 (m, 2H), 7.27-7.33 (m, 2H), 7.39(t, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.65 (dd, J=8.8, 3.2 Hz, 1H).

34. Preparation of6-(4-Fluoro-phenyl)-3-iodo-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

N-iodosuccinimide (73.4 mg, 0.33 mmol) was added to a stirred solutionof6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(0.1 g, 0.3 mmol) in a mixture of ACN (2 mL) and acetic acid (2 mL). Themixture was stirred at RT for 3 days. The mixture was diluted with DCMand washed with a saturated solution of Na₂CO₃. The organic layer wasseparated, dried (Na₂SO₄), filtered and the solvents evaporated invacuo. The crude product was triturated with MeOH to yield6-(4-fluoro-phenyl)-3-iodo-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(46 mg, 56% yield) as a brown solid, that was used in the next stepwithout further purification.

35. Preparation of3-Chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

N-chlorosuccinimide (30.5 mg, 0.23 mmol) was added to a stirred solutionof6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(0.1 g, 0.3 mmol) in DMF (3.25 mL). The mixture was stirred at 150° C.for 20 minutes under microwave irradiation. The solvent was evaporatedin vacuo and the crude product was purified by flash columnchromatography (silica; AcOEt in DCM with a gradient of 0/100 to 15/85).The desired fractions were collected and the solvents evaporated invacuo to yield3-chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(21 mg, 27% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) 8 ppm 3.27(t, J=6.6 Hz, 2H), 3.99 (t, J=6.6 Hz, 2H), 4.99 (s, 2H), 6.95-7.01 (m,1H), 7.01-7.07 (m, 2H), 7.09-7.17 (m, 2H), 7.27-7.36 (m, 4H).

36. Preparation of3-Bromo-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

Benzoyl peroxide (7.2 mg, 0.03 mmol) was added to a stirred solution ofN-bromosuccinimide (30.58 mg, 0.33 mmol) and6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(0.1 g, 0.3 mmol) in DCE (5 mL). The mixture was stirred at RT for 16hours. The solvent was evaporated in vacuo and the crude product waspurified by flash column chromatography (silica; AcOEt in DCM with agradient of 0/100 to 10/90). The desired fractions were collected andthe solvents evaporated in vacuo to yield3-bromo-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(57 mg, 35% yield) as a white solid.

37. Preparation of6-(4-Fluoro-phenyl)-3-methyl-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one

Tetrakis(triphenylphosphine)palladium(0) (6.4 mg, 0.0055 mmol) was addedto a stirred suspension of3-bromo-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(116 mg, 0.18 mmol), methylboronic acid (55.05 mg, 0.92 mmol) and K₂CO₃(76.3 mg, 0.23 mmol) in a mixture of 1,4-dioxane (7.07 mL) and DMF (1.77mL) under nitrogen and in a sealed tube. The mixture was stirred at 150°C. for 45 minutes under microwave irradiation. The solvents wereevaporated in vacuo and the crude product was purified by flash columnchromatography (silica; 7 M solution of ammonia in MeOH in DCM with agradient of 0/100 to 1.5/98.5 and then AcOEt in DCM with a gradient of0/100 to 10/90). The desired fractions were collected and the solventsevaporated in vacuo. The product was purified by RP HPLC (C18 XBridge19×100 5 um, gradient from 80% of 0.1% solution of ammoniumformate/ammonium hydroxide buffer pH 9 solution in water and 20% CH₃CNto 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH9 solution in water and 100% MeOH) to yield6-(4-fluoro-phenyl)-3-methyl-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one(36.5 mg, 56% yield). ¹H NMR (400 MHz, CDCl₃) 8 ppm 2.52 (s, 3H), 3.26(t, J=6.5 Hz, 2H), 3.98 (t, J=6.6 Hz, 2H), 4.96 (s, 2H), 6.97 (br. t,J=7.4, 7.4 Hz, 1H), 7.00-7.06 (m, 2H), 7.09-7.18 (m, 2H), 7.27-7.37 (m,4H).

38. Compounds

Compounds were synthesized represented by the formula:

wherein Ar¹ and R³ were as described in Table 111 below. R^(2a), R⁴,R^(5a), and R^(5b) were H, and

R^(1a) was as indicated in the table. The synthetic methods used toprepare the indicated were as described in the preceding examples with areference example method as noted in the table.

Compounds were synthesized represented by the formula:

wherein Ar¹ and R³ were as described in Table IV below. R^(1a), R^(1b),R^(2a), R^(2b), R⁴, R^(5a), and R^(5b) were H. The synthetic methodsused to prepare the indicated were as described in the precedingexamples with a reference example method as noted in the table.

Analytical data for the numbered compound in Table V corresponds to thenumber given in the first column of either Table 111 or Table IV. LCMS:[M+H]+ means the protonated mass of the free base of the compound; Rtmeans retention time (in minutes); and Method refers to the LCMS methodused.

TABLE III Compound Reference Number Ar¹ R³ R^(1a) R^(2a) R⁴ Example* 1

H H H H 6 2

—CH₃ H H H 23 3

H H H 23 4

H H H 23 5

H H H 23 6

H H H 23 7

H H H 23 8

H H H 24 9

H H H 24 10

H H H 24 11

H H H 24 12

H H H 23 13

H H H 23 14

H H H 23 15

H H H 24 16

H H H 23 17

H H H 23 18

H H H 23 19

H H H 23 20

F H H 23 21

H H H 23 22

H H H 23 23

H H H 24 24

H H H 24 25

H H H 25 26

I H H 23 27

CH₃ H H 26 28

H CH₃ H 23 29

H H Cl 27 30

H H Br 23 *Reference Example 6 is2-phenoxymethyl-6H-imidazo[1,2-C]pyrimidin-5-one; Reference Example 23is 6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 24 is6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 25 is6-(2-methoxy-pyrimidin-4-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 26 is6-(4-fluoro-phenyl)-8-methyl-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one;and, Reference Example 27 is3-chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one.The reference example corresponds to the numbering of synthetic examplesabove, and is not the same as the number for compound number as given inTables I-V.

TABLE IV Compound Reference Number Ar¹ R³ R⁴ Example* 31

H 28 32

H 28 33

H 29 34

H 29 35

H 30 36

H 31 37

H 32 38

H 33 39

H 33 40

H 33 41

I 34 42

Cl 35 43

Br 36 44

CH₃ 37 *Reference Example 28 is6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 29 is2-(3-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 30 is2-(4-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 31 is6-(5-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 32 is6-(4-fluoro-phenyl)-2-m-tolyloxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 33 is6-(5-fluoro-6-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 34 is6-(4-fluoro-phenyl)-3-iodo-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 35 is3-chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;Reference Example 36 is3-bromo-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one;and, Reference Example 37 is6-(4-fluoro-phenyl)-3-methyl-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one.

TABLE V Compound M.p LCMS Number (° C.) [M + H]⁺ R_(t) Method 1 n.d. 2421.19 1 2 130.9 256 1.47 1 3 142.3 336 2.41 1 4 123.4 336 2.45 1 5 296.6354 2.62 1 6 141.1 354 2.55 1 7 122.3 3.32 2.59 1 8 >300 333 2.49 2 9n.d. 337 2.42 2 10 199.5 351 2.74 2 11 209.4 333 2.50 2 12 >300 293 3.502 13 165.0 361 2.49 2 14 163.4 354 2.69 2 15 239.4 333 2.42 2 16 >300404 3.19 2 17 102.1 296 2.45 2 18 282.3 337 2.15 2 19 >300 337 1.70 2 20110.7 354 2.88 2 21 141.8 420 3.49 2 22 189.4 411 2.91 2 23 203.1 3512.64 2 24 136.0 362 2.97 2 25 171.2 350 1.90 3 26 n.d. 462 3.84 5 27146.9 350 2.88 2 28 143.6 350 2.63 2 29 170.3 370 3.01 2 30 n.d. 4143.21 2 31 195.2 338 2.33 1 32 >300 338 2.43 1 33 165.4 356 2.55 1 34141.1 355 2.50 1 35 182.3 356 3.37 4 36 n.d. 335 2.45 2 37 169.3 3522.84 2 38 n.d. 353 2.68 2 39 135.0 339 2.32 2 40 196.5 353 2.59 2 41n.d. 464 3.68 5 42 200.1 372 2.88 2 43 n.d. 416 3.65 5 44 160.4 352 2.752

39. Generation of Human mGluR5 Stable Cell Line

Human mGluR5a cDNA in pCMV6-XL6 mammalian expression plasmid waspurchased from OriGene Technologies, Inc. (catalogue number SC326357)and subcloned into pcDNA3.1(−). Human embryonic kidney (HEK)293A cellswere then transfected with human mGluR5a pcDNA3.1(−) usingLipofectAmine-2000 (Invitrogen) and monoclones were selected and testedfor functional response using a Ca²⁺ mobilization assay. Monoclones werenamed for the species (“H” for human) plus the location on the plate(e.g. “10H”).

40. Cell-Based Functional Assay

HEK cells transfected with the human mGluR5a receptor (H10H or H12H cellline) were plated at 15,000 cells/well in clear-bottomedpoly-D-lysine-coated assay plates (BD Falcon) inglutamate-glutamine-free growth medium and incubated overnight at 37° C.and 5% CO₂. Cell-lines used were either the H10H or H12H cell-linesexpressing the human mGluR5 receptor. The following day, the growthmedium was removed and the cells were washed with assay buffercontaining 1× Hank's balanced salt solution (Invitrogen, Carlsbad,Calif.), 20 mM HEPES, 2.5 mM probenecid, pH 7.4 and left with 20 μL ofthis reagent. Following this step, the cells were loaded with calciumindicator dye, fluo-4 AM, to a final concentration of 2 μM and incubatedfor 40-45 min at 37° C. The dye solution was removed and replaced withassay buffer. Cell plates were held for 10-15 min at room temperatureand were then loaded into the Functional Drug Screening System 6000(FDSS 6000, Hamamatsu, Japan).

After establishment of a fluorescence baseline for about 3 seconds, thecompounds of the present invention were added to the cells, and theresponse in cells was measured. 2.3 minutes later an EC₂₀ concentrationof the mGluR5 receptor agonist glutamate was added to the cells, and theresponse of the cells was measured for about 1.7 minutes. All testcompounds were dissolved and diluted to a concentration of 10 mM in 100%DMSO and then serially diluted into assay buffer for a 2× stock solutionin 0.6% DMSO; stock compounds were then added to the assay for a finalDMSO concentration of 0.3% after the first addition to the assay well.Calcium fluorescence measures were recorded as fold over basalfluorescence; raw data was then normalized to the maximal response toglutamate. Potentiation of the agonist response of the mGluR5 receptorin the present invention was observed as an increase in response tosubmaximal concentrations of glutamate in the presence of compoundcompared to the response to glutamate in the absence of compound.

41. Data Analysis

The concentration-response curves of compounds of the present invention,obtained in the presence of EC₂₀ of mGluR5 receptor agonist glutamate todetermine positive allosteric modulation, were generated using MicrosoftExcel with IDBS XLfit add-ins. The raw data file containing all timepoints was used as the data source in the analysis template. This wassaved by the FDSS as a tab-delimitted text file. Data were normalizedusing a static ratio function (F/F₀) for each measurement of the total350 values per well divided by each well's initial value. Data was thenreduced as to peak amplitudes (Max—Initial Min) using a time range thatstarts approximately 1 second after the glutamate EC₂₀ addition andcontinues for approximately 40 seconds. This is sufficient time tocapture the peak amplitude of the cellular Calcium response. Individualamplitudes were expressed as % E_(Max) by multiplying each amplitude by100 and then dividing the product by the mean of the amplitudes derivedfrom the glutamate EC_(Max)-treated wells. pEC₅₀ values for testcompounds were generated by fitting the normalized values versus the logof the test compound concentration (in mol/L) using a 4 parameterlogistic equation where none of the parameters were fixed. Each of thethree values collected at each concentration of test compound wereweighted evenly. Individual values falling outside the 95% predictionlimits of the curve fit were automatically excluded from the fit. Acompound was designated as a positive allosteric modulator if thecompound showed a concentration-dependent increase in the glutamate EC₂₀addition. % E_(Max) for compounds may be estimated using the resultingcorresponding parameter value determined using the curve fit or bytaking an average of the overall maximum response at a singleconcentration. These two methods are in good agreement for curves with aclear plateau at the high concentration range. For data that show anincrease in the EC₂₀ response, but, do not hit a plateau, the average ofthe maximum response at a single concentration is preferred. Forconsistency purposes across the range of potencies observed, all E_(Max)values reported in this application are calculated using the maximumaverage response at a single concentration. The E_(max) (%) value foreach compound reported in this application is defined as the maximum %effect obtained in a concentration-response curve of that compoundexpressed as a percent of the response of a maximally effectconcentration of glutamate. Tables I and II above shows thepharmacological data obtained for a selected set of compounds.

For compounds showing a lower potency (e.g. as indicated by a lack of aplateau in the concentration response curve), but with a greater than a20% increase in glutamate response, a potency of >10 μM (pEC₅₀<5) wasestimated.

42. Prospective in Vivo Effects

Generally clinically relevant antipsychotic agents (both typical andatypical) display efficacy in preclinical behavior challenge models. Invivo effects of the compounds described in the preceding examples areexpected to be shown in various animal behavioural challenge modelsknown to the skilled person, such as amphetamine-induced orphencyclidine (PCP)-induced hyperlocomotion, and other models, such asNMDA receptor antagonist MK-801-induced locomotor activity. These modelsare typically conducted in rodent, such as rat or mouse, but may beconducted in other animal species as is convenient to the study goals.Compounds, products, and compositions disclosed herein are expected toshow in vivo effects in various animal behavioural challenge modelsknown to the skilled person, such as amphetamine-induced orphencyclidine (PCP)-induced hyperlocomotion in rodent, and other models,such as NMDA receptor antagonist MK-801-induced locomotor activity.These models are typically conducted in rodent, such as rat or mouse,but may be conducted in other animal species as is convenient to thestudy goals.

For example, compounds having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when is present and A¹ and A² are joined by acovalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2c), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof, are expected to show such in vivoeffects.

Moreover, compounds prepared using the disclosed synthetic methods arealso expected to show such in vivo effects.

43.6-(4-fluorophenyl)-2-(phenoxymethyl)-7,8-dihydroimidazo[1,2-c]pyrimidin-5(6H)-oneActivity in Induced Hyperlocomotion Animal Model

Locomotor activity was assessed as mean distance traveled (cm) instandard 16×16 photocell testing chambers measuring 43.2 cm(Length)×43.2 cm (Width)×30.5 cm (Height) (Med Associates, St. Albans,Vt.). Animals were habituated to individual activity chambers for atleast 30 min prior to drug administration. Following administration ofdrug or vehicle, activity was recorded for a 90 minute time period. Datawas expressed as the mean (±SEM) distance traveled recorded in 5 minintervals over the test period. The data was analyzed using repeatedmeasures analysis of variance (ANOVA) followed by post-hoc testing usingDunnett's test, when appropriate. A difference was consideredsignificant when p≦0.05.

Amphetamine sulfate was obtained from Sigma (Cat#A5880-1G; St. Louis,Mo.) and 10 mg was dissolved in 10 ml of water. The test compound,6-(4-fluorophenyl)-2-(phenoxymethyl)-7,8-dihydroimidazo[1,2-c]pyrimidin-5(6H)-one(labeled as “Test Compound” in FIG. 4), was formulated in a volume of 10ml with an amount of drug appropriate to the dosage indicated. Theappropriate amount of compound was mixed into a 20%2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD; indicated as “BCD” in FIG. 4)solution. The solution was formulated so that animals were injected witha volume equal to about 10× body weight. The mixture was thenultrahomogenized on ice for 2-3 minutes using the Dismembrator (FisherScientific Model 150T). Then the pH was checked using 0-14 EMD stripsand adjusted to a pH of 6-7 if necessary. The mixture was then vortexedand stored in a warm sonication bath until time to be injected. Animalswere administered samples of the following: (a) Amphetamine sulfate, 1mg/kg, administered subcutaneously; and, (b)6-(4-fluorophenyl)-2-(phenoxymethyl)-7,8-dihydroimidazo[1,2-c]pyrimidin-5(6H)-one,at the doses as indicated in FIG. 4 (indicated as “Test Compound”therein), and was administered by oral gavage.

The study was carried out using male Sprague-Dawley rats weighing 225g-275 g, between 2-3 months old (Harlan, Inc., Indianapolis, Ind.), wereused. The number of animals used is as indicated in FIG. 4. They werekept in the animal care facility certified by the American Associationfor the Accreditation of Laboratory Animal Care (AALAC) under a 12-hourlight/dark cycle (lights on: 6 a.m.; lights off: 6 p.m.) and had freeaccess to food and water. The experimental protocols performed duringthe light cycle were approved by the Institutional Animals Care and UseCommittee of Vanderbilt University and conformed to the guidelinesestablished by the National Research Council Guide for the Care and Useof Laboratory Animals.

The animals were habituated in Smart Open Field locomotor activity testchambers (Hamilton-Kinder, San Diego, Calif.) with 16×16 photobeams toautomatically record locomotor activity for 30 min and then dosed withvehicle or test compound. The rats were then placed into cages. At 60min, all rats were injected subcutaneously with 1 mg/kg amphetamine orvehicle and then monitored for an additional 60 min. Animals aremonitored for a total of 120 minutes. Data are expressed as changes inambulation defined as total number of beam breaks per 5 min periods.

The data for the dose-response studies were analyzed by a between-groupanalysis of variance. If there was a main effect of dose, then each dosegroup was compared with the vehicle amphetamine group. The calculationswere performed using JMP IN 8 (SAS Institute, Cary, N.C.) statisticalsoftware and graphed using SigmaPlot9 (Saugua, Mass.). Dose-dependentresults for reversal of amphetamine-induced hyperlocomotion by6-(4-fluorophenyl)-2-(phenoxymethyl)-7,8-dihydroimidazo[1,2-c]pyrimidin-5(6H)-oneare shown in FIG. 4. The following abbreviations are used: (a) “Testcompound” refers to6-(4-fluorophenyl)-2-(phenoxymethyl)-7,8-dihydroimidazo[1,2-c]pyrimidin-5(6H)-one;(b) subcutaneous administration of compound is indicated by “sc”; (c)oral gavage administration is indicated by “po”; and (d) amphetaminesulfate is indicated as “Amphetamine.” The time of administration ofamphetamine sulfate is indicated in FIG. 4 by “AMP” and thecorresponding arrow. The vehicle for test compound is 20% wt/v HP-β-CD(indiocated as “BCD” in FIG. 4), and the vehicle for amphetamine issterile water.

44. Prophetic Pharmaceutical Composition Examples

“Active ingredient” as used throughout these examples relates to one ormore compounds having a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalo, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl; wherein when ----- is present and A¹ and A² are joined bya covalent double bond, A¹ is CR^(1a), and A² is CR^(2a); wherein R^(1a)is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; wherein R^(2a) is selected from hydrogen, C1-C4alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when -----is not present and A¹ and A² are joined by a covalent single bond, A¹ isCR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein each of R^(1b) andR^(1c) are independently selected from hydrogen, fluoro, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) and R^(1c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein each ofR^(2b) and R^(2c) are independently selected from hydrogen, C1-C4 alkyl,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(2b) and R^(2c) arecovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered spirocycloalkyl; wherein R^(1a)and R^(2a), when present, are optionally covalently bonded and, togetherwith the intermediate atoms, comprise an optionally substituted 3- to7-membered fused cycloalkenyl; wherein R^(1b) and R^(2b), when present,are optionally covalently bonded and, together with the intermediateatoms, comprise an optionally substituted 3- to 7-membered fusedcycloalkyl; wherein R³, when ----- is present, is selected fromhydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6 monohaloalkyl; C1-C6polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8cycloalkyl)-C1-C6 alkyl-; (C3-C8 heterocycloalkyl)-C1-C6 alkyl-, andaromatic moiety Ar²; wherein Ar² is phenyl or benzyl or —(C2-C6)-phenyl,and substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl),or Ar² is monocyclic heteroaryl substituted with 0-3 substituentsindependently selected from halo, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and—N(C1-C4 alkyl)(C1-C4 alkyl); and, wherein R³, when ----- is notpresent, is Ar²; wherein R⁴ is selected from hydrogen, halogen, cyano,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino,C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptablesalt, solvate, or polymorph thereof. The following examples of theformulation of the compounds of the present invention in tablets,suspension, injectables and ointments are prophetic. Typical examples ofrecipes for the formulation of the invention are as given below.

a. Tablets

A tablet can be prepared as follows:

Component Amount Active ingredient 5 to 50 mg Di-calcium phosphate 20 mgLactose 30 mg Talcum 10 mg Magnesium stearate 5 Potato starch add tomake total weight 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

b. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

c. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

d. Ointment

An ointment can be prepared as follows:

Component Amount Active ingredient 5 to 1000 mg Stearyl alcohol 3 gLanoline 5 g White petroleum 15 g Water add to make total weight 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A compound having a structure represented by aformula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2a) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.
 2. The compound of claim 1, having a structurerepresented by a formula:


3. The compound of claim 1, having a structure represented by a formula:


4. The compound of claim 1, having a structure represented by a formula:

wherein R⁷ and R⁸ are independently selected from hydrogen and C1-C4alkyl.
 5. The compound of claim 1, having a structure represented by aformula:

wherein R⁶ is C1-C4 alkyl.
 6. The compound of claim 1, having astructure represented by a formula:


7. The compound of claim 1, having a structure represented by a formula:


8. The compound of claim 1, having a structure represented by a formula:


9. The compound of claim 1, having a structure represented by a formula:


10. The compound of claim 1, having a structure represented by aformula:


11. The compound of claim 1, having a structure represented by aformula:

wherein R⁷ and R⁸ are independently selected from hydrogen and C1-C4alkyl.
 12. The compound of claim 1, having a structure represented by aformula:

wherein R⁶ is C1-C4 alkyl.
 13. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 14. A method for the treatment of aneurological and/or psychiatric disorder associated with glutamatedysfunction in a mammal comprising the step of administering to themammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.
 15. The method of claim 14, wherein the disorderis a neurological and/or psychiatric disorder associated with mGluR5dysfunction.
 16. The method of claim 15, wherein the disorder isselected from dementia, delirium, amnestic disorders, age-relatedcognitive decline, schizophrenia, psychosis including schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, substance-related disorder, movementdisorders, epilepsy, chorea, pain, migraine, diabetes, dystonia,obesity, eating disorders, brain edema, sleep disorder, narcolepsy,anxiety, affective disorder, panic attacks, unipolar depression, bipolardisorder, and psychotic depression.
 17. A method for the treatment of adisease of uncontrolled cellular proliferation in a mammal comprisingthe step of administering to the mammal a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein ----- is an optional covalent bond, wherein valence issatisfied; wherein Ar¹ is phenyl substituted with 0-3 substituentsindependently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy,C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ar¹ is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, andC1-C4 polyhaloalkyl; wherein when ----- is present and A¹ and A² arejoined by a covalent double bond, A¹ is CR^(1a), and A² is CR^(2a);wherein R^(1a) is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R^(2a) is selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;wherein when ----- is not present and A¹ and A² are joined by a covalentsingle bond, A¹ is CR^(1b)R^(1c), and A² is CR^(2b)R^(2c); wherein eachof R^(1b) and R^(1c) are independently selected from hydrogen, fluoro,C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R^(1b) andR^(1c) are covalently bonded and, together with the intermediate atoms,comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R^(2b) and R^(2c) are independently selected fromhydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, orR^(2b) and R^(2c) are covalently bonded and, together with theintermediate atoms, comprise an optionally substituted 3- to 7-memberedspirocycloalkyl; wherein R^(1a) and R^(2a), when present, are optionallycovalently bonded and, together with the intermediate atoms, comprise anoptionally substituted 3- to 7-membered fused cycloalkenyl; whereinR^(1b) and R^(2b), when present, are optionally covalently bonded and,together with the intermediate atoms, comprise an optionally substituted3- to 7-membered fused cycloalkyl; wherein R³, when ----- is present, isselected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy; C1-C6monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8heterocycloalkyl; (C3-C8 cycloalkyl)-C1-C6 alkyl-; (C3-C8heterocycloalkyl)-C1-C6 alkyl-, and aromatic moiety Ar²; wherein Ar² isphenyl or benzyl or —(C2-C6)-phenyl, and substituted with 0-3substituents independently selected from halogen, cyano, C1-C4 alkyl,C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, —NH₂,—NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl), or Ar² is monocyclicheteroaryl substituted with 0-3 substituents independently selected fromhalogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, —NH₂, —NH(C1-C4 alkyl), and —N(C1-C4 alkyl)(C1-C4 alkyl);and, wherein R³, when ----- is not present, is Ar²; wherein R⁴ isselected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4dialkylamino, and C1-C4 alkoxy; wherein each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate,or polymorph thereof.
 18. The method of claim 17, wherein the disease iscancer.
 19. The method of claim 17, wherein the disease is selected frombreast cancer, renal cancer, gastric cancer, and colorectal cancer. 20.The method of claim 17, wherein the disease is selected from lymphoma,cancers of the brain, genitourinary tract cancer, lymphatic systemcancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breastcancer, and malignant melanoma.